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η analysis and evaluation of the scientific aspects of drug discovery .... peutic use in the United States today. Progress in population control and ...
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2 Drugs from Natural Products—Animal Sources J. A . H O G G

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The Upjohn C o . , Kalamazoo, M i c h . 49001

Comparative through and

the

analysis

prostaglandin

certain

developments

reveals

some

genesis.

of

the

timetables

events in the development

the

break­

when field

viewed

hormone

in relation

of science

as a

factors

which

most influenced

their

factor

in regulating

pace

was the emergence

in other fields of science. served to stimulate

of new supporting

The breakthrough

the pace.

Despite

the

technology

event itself

numerous

the influence

of advances

is recognizable.

of the steroid in the science The

potential

but

of drug discovery

in

for drug

high as judged

of numerous

fields.

new

effort

developments,

from animal sources remains emerging

often

similarities

between the two fields the pattern of the prostaglandin has not been a duplication general

to

whole,

The most prominent

of progress

of

fields, in the

depicting

of the steroid

by the

discovery promise

η analysis a n d e v a l u a t i o n o f the scientific aspects of d r u g d i s c o v e r y f r o m a n i m a l o r i g i n s h o u l d p r o v i d e some e n l i g h t e n m e n t o n t h e f u t u r e of this d r u g source.

M o s t of t h e major classifications of d r u g c a n d i d a t e

substances k n o w n to b e p r o d u c e d b y t h e v a r i o u s a n i m a l categories ( T a b l e I ) are s t i l l u n d e r a c t i v e i n v e s t i g a t i o n t o d a y . H o w e v e r , since this entire

field

is so vast, o n l y t w o categories are d i s c u s s e d : t h e steroid

h o r m o n e field a n d the p r o s t a g l a n d i n s .

T h e f o r m e r is o l d e r i n v i n t a g e

a n d m o r e m a t u r e i n its d e v e l o p m e n t w h i l e t h e latter is a field i n w h i c h there are as yet no p r o d u c t s i n t h e r a p e u t i c use. N e i t h e r category is l i m i t e d i n o r i g i n t o m a m m a l i a n s a n d i n t h e case of steroids n o t e v e n to a n i m a l s . T h e s e t w o e x c i t i n g fields of d r u g research are a n a l y z e d b y u s i n g timetables f o r e a c h w h i c h d e p i c t b r e a k t h r o u g h events.

Perhaps

some

of t h e lessons l e a r n e d f r o m t h e steroid experience m a y b e u s e d i n d e v e l ­ o p i n g the p r o s t a g l a n d i n s . 14

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

HOGG

Animal

Table I. Animal

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15

Sources Drugs from Animal Sources Drug (Candidate) Substances

Category

Vertebrates aquatic terrestrial

steroid hormones peptide hormones vitamins enzymes

Invertebrates aquatic t e r r e s t r i a l (e.g., insects)

vaccines prostaglandins miscellaneous pheromones p r e d a t o r - p r e y defense p a r a s i t e - h o s t defense

Steroid Hormones F i g u r e 1 shows t h e basic c a r b o n structures f o r these t w o classes of substances. A l l steroids c o n t a i n t h e

perhydrocyclopentanophenanthrene

r i n g system w h i l e t h e c a r b o n skeleton basic to a l l p r o s t a g l a n d i n s has b e e n c a l l e d p r o s t a n o i c a c i d . T h e s t e r o i d h o r m o n e s are discussed

PERHYDROCYCLOPENTANOPHENANTHRENE

Figure

1.

Basic carbon

first.

PROSTANOIC ACID

skeletons of steroids glandins

and

prosta-

T h e sequence of events w h i c h n o r m a l l y occurs i n the d i s c o v e r y of a n a t u r a l l y o c c u r r i n g substance is u s u a l l y i n i t i a t e d b y some

biological

event w h i c h signals t h e p o s s i b i l i t y of d r u g p o t e n t i a l . T h i s " b i o d e t e c t i o n " e n d p o i n t m a y o r m a y n o t r e v e a l a specific area of m e d i c i n a l interest f o r the u n k n o w n substance.

I n some instances t h e i n i t i a l b i o l o g i c a l a c t i v i t y

c a n b e d e v e l o p e d i n t o a q u a n t i t a t i v e assay m e t h o d , w h i c h c a n t h e n b e u s e d to g u i d e the i s o l a t i o n of active substance.

M o s t h o r m o n a l substances

are present i n t i n y amounts so that i s o l a t i o n cannot b e a c h i e v e d w i t h o u t the h e l p of s u c h a n assay. T h i s is e s p e c i a l l y true f o r t h e p r i m a r y steroid h o r m o n e s s h o w n i n T a b l e I I . T h e i s o l a t i o n o f estrone w o u l d h a v e b e e n m u c h d e l a y e d h a d Z o n d e k n o t d i s c o v e r e d that the u r i n e of p r e g n a n t w o m e n is a m u c h r i c h e r source t h a n o v a r i a n extract, w h e r e its presence h a d first b e e n

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

detected.

16

DRUG

DISCOVERY

T h e m a g n i t u d e of the task i n v o l v e d i n one of these isolations c a n

be

a p p r e c i a t e d f r o m the fact that B u t e n a n d t was a b l e to isolate o n l y 20 m g of p u r e progesterone f r o m 625 k g of ovaries o b t a i n e d f r o m 50,000 sows. T h e large scale extractions w e r e c a r r i e d out b y S c h e r i n g A G laboratories. T h e first testicular h o r m o n e isolated was androsterone, a m e t a b o l i t e of testosterone.

T h i s also w a s a c h i e v e d b y B u t e n a n d t starting w i t h a n

extract f r o m 15,000 liters of u r i n e s u p p l i e d b y S c h e r i n g f r o m w h i c h he o b t a i n e d o n l y 15 m g of p u r e crystals.

F o u r years later, L a q u e r isolated

10 m g of the p r i m a r y m a l e sex h o r m o n e , testosterone, f r o m 100 k g of Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

steer testis. I n a l l cases o n this table the k e y to i s o l a t i o n w a s the q u a n t i t a t i v e bioassay as l i s t e d . Table II.

Source Concentrations of Steroid Hormones

Hormone Estrone

Concentration

Source human pregnancy urine pregnant mare urine palm kernel

Progesterone

sow ovaries

Testosterone

Hydrocortisone

urine

beef a d r e n a l

1 mg/liter

Assay A l l e n - D o i s y (1)

10 m g / l i t e r 18 mg/50 k g 625 k g y i e l d e d 20 m g

C o r n e r - A l l e n (2)

1 mg/liter (15,000 liters y i e l d e d 15 m g ( 5 )

C o x c o m b test

37 mg/1000 l b

Ingle w o r k test (4)

T h e dates of these isolations a n d others of the p r i m a r y s t e r o i d horm o n e g r o u p are r e c o r d e d i n T a b l e III.

T h i s o v e r a l l t i m e t a b l e of events

also shows other k e y stages i n the d i s c o v e r y a n d d e v e l o p m e n t of drugs f r o m n a t u r a l sources.

M o s t of these stages n o r m a l l y o c c u r b u t not a l w a y s

i n the o r d e r l i s t e d . The members s i m i l a r i n structure.

of this g r o u p of n a t u r a l l y o c c u r r i n g hormones

are

I n their b i o c h e m i c a l e v o l u t i o n nature has u s e d a

c o m m o n r a w m a t e r i a l — n a m e l y , cholesterol, yet their p h y s i o l o g i c a l roles are vastly different. It w o u l d seem that nature is the o r i g i n a l p r a c t i t i o n e r of m o l e c u l a r m o d i f i c a t i o n . T h e most s t r i k i n g fact r e v e a l e d o n this chart is that the i s o l a t i o n , structure, a n d p a r t i a l synthesis of a l l of the p r i m a r y hormones i n each class, e x c e p t i n g aldosterone, w e r e a c h i e v e d c o n c u r r e n t l y w i t h i n the 1930's, a ten-year p e r i o d . It w o u l d be t e m p t i n g to assume f r o m this t a b l e that structure d e t e r m i n a t i o n a n d synthesis are r o u t i n e consequences of the isolation.

T h e isolations of this entire g r o u p , e x c e p t i n g aldosterone,

c u r r e d rather close together.

oc-

H o w e v e r , the reasons w h i c h e x p l a i n the

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

Animal

HOGG

17

Sources

Table III.

Steroid Hormones—Discovery Development (Timetable)"

and

50

54

58

62

1

1

1

1

19 30

(i)

Estrone

(i)

M a l e Hormones Testosterone Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

(2)

(4)

(5,6)

(4)

(1,2,3,6)

(4)

(30) (1)(2) (2,3)

(3)

" L e g e n d : (1) i s o l a t i o n , (2) structure, (3) t h e r a p e u t i c use, (6) analogs.

(5 )

(4) (6) (4)

(1)

(1,2)

Aldosterone (5)

46

1

( 3)

(2,6) (5) (3) (1,2,3)

Progesterone

DOC

42

38

1

Female Hormones Equilenin

A d r e n a l Steroids Cortisone

34

p a r t i a l synthesis. (4)

(4) t o t a l synthesis,

r a p i d b r e a k t h r o u g h s i n structure a n d synthesis seen here relate to p r e c e d i n g events a n d are of c o n s i d e r a b l e i m p o r t a n c e to the process of n a t u r a l p r o d u c t d r u g d i s c o v e r y . T h e s e reasons are discussed b e l o w . T h e t o t a l synthesis of these substances l a g g e d another d o z e n years a n d t h e n b r o k e across the b o a r d . G i f t e d scientists i n b o t h i n d u s t r y a n d universities w e r e responsible for d e v e l o p i n g the necessary

technology.

Scientists i n b o t h e n v i r o n m e n t s w e r e m o t i v a t e d b y the c h a l l e n g e

and

i m p o r t a n c e of the goals set u p b y the successes of the steroid h o r m o n e decade.

T h e risk for the i n d u s t r i a l scientist to b e c o m e i n v o l v e d at this

early stage is greater since he is also a c c o u n t a b l e for the p r a c t i c a l i t y of his results. T h e t h e r a p e u t i c u t i l i z a t i o n of steroids d i d not r e a c h significant p r o portions u n t i l the early 1950's, f o l l o w i n g the cortisone b r e a k t h r o u g h i n 1949.

M e r c k a n d C o . assumed the p r i m a r y risk for d e v e l o p i n g m e t h o d -

o l o g y a n d p r e p a r i n g large quantities of cortisone f o r c l i n i c a l e v a l u a t i o n . H e n c h , at the M a y o C l i n i c , t h e n d i s c o v e r e d the c l i n i c a l efficacy of c o r t i sone i n r e l i e v i n g the s y m p t o m s of arthritis.

O n e immediately obvious

c o n s e q u e n c e of this b r e a k t h r o u g h , n o w w e l l k n o w n , was a w o r l d - w i d e , u p w a r d surge of s t e r o i d research i n general a n d a d r e n a l steroid research in particular. I n a d d i t i o n to the c o m p e t i t i o n to exploit the m e d i c a l markets so l o n g sought for, other t e c h n i c a l factors c o n t r i b u t e d to the research b u i l d u p t h r o u g h the 1950's. T h e n o w r e a d i l y a v a i l a b l e steroid substances w e r e i d e a l m o d e l s to s t u d y stereochemistry,

reaction mechanisms

a n d rates,

c o n f o r m a t i o n a l analysis, a n d the a p p l i c a t i o n of n e w instruments to structure c h a r a c t e r i z a t i o n . A l l of these studies, a l t h o u g h not necessarily a i m e d

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

18

DRUG

DISCOVERY

at d r u g d i s c o v e r y , w e r e nonetheless c o n t r i b u t o r y . Scientific b r e a k t h r o u g h c o n t i n u e d to a d d f u e l to the fire. T h e m i c r o b i o l o g i c a l 11-oxygenation of Peterson a n d M u r r a y ( 5 )

i n 1952 greatly e x p a n d e d the t e c h n i c a l c a p a -

b i l i t y to p r o d u c e steroids.

T h e synthesis of the h i g h l y active 9-fluoro

a n a l o g of h y d r o c o r t i s o n e i n 1954 b y F r i e d (6)

was the f o r e r u n n e r of a

vast a d r e n a l steroid a n a l o g p r o g r a m . H o w e v e r , the concept of m o l e c u l a r m o d i f i c a t i o n (i.e., analogs)

was not n e w to the steroid

stilbestrol was s y n t h e s i z e d b y C o o k ( 7 )

field.

Diethyl-

at a b o u t the t i m e the

estrone

structure w a s e l u c i d a t e d , p r e s u m a b l y not b y d e s i g n b u t i n c o n n e c t i o n Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

w i t h studies o n the structure of estrone.

Probably few analog programs

c a n m a t c h the scope of the m o d i f i e d estrogen p r o g r a m t h a t f o l l o w e d . M e t h y l t e s t o s t e r o n e was s y n t h e s i z e d i n the same year that saw the b i r t h of testosterone itself.

Steroids are still b e i n g c h e m i c a l l y m o d i f i e d t o d a y .

Some i n d i c a t i o n of the m a g n i t u d e of the steroid effort is n o t e d b y F i e s e r a n d F i e s e r ( 8 ) , w h o o b s e r v e d that even as early as 1936 p u b l i c a tions w e r e a p p e a r i n g at the rate of 300 per year. that i n 1960 there w e r e 1,123

A p p l e z w e i g (9)

notes

r e p o r t e d analogs e m u l a t i n g the n a t u r a l

hormones. T a b l e I V p r o v i d e s a q u i c k v i s u a l i m p r e s s i o n of some 50 or 60 separate d r u g entities, e x c l u d i n g d e r i v a t i v e s a n d f o r m u l a t i o n s , a v a i l a b l e for therap e u t i c use i n the U n i t e d States t o d a y .

Progress i n p o p u l a t i o n c o n t r o l

a n d f a m i l y p l a n n i n g w a s c e r t a i n l y e n h a n c e d b y the d e v e l o p m e n t of the steroid-based p i l l , w h i c h contains progestins a n d estrogens.

However,

the entire steroid h o r m o n e d e v e l o p m e n t w o u l d have b e e n d e l a y e d m a r k e d l y h a d it not b e e n for p r e c e d i n g d e v e l o p m e n t s , o u t l i n e d i n T a b l e V . T h e h i g h l i g h t s i n the l o n g h i s t o r y of research

that p r e c e d e d

the

steroid h o r m o n e era of the 1930's are s h o w n here. T h i s t i m e t a b l e records the d i s c o v e r y a n d c h a r a c t e r i z a t i o n of a select f e w f r o m l i t e r a l l y h u n d r e d s of n a t u r a l l y o c c u r r i n g steroid substances,

w h i c h w e r e later to

become

i m p o r t a n t as r a w materials i n man's p r e o c c u p a t i o n w i t h steroid synthesis. D u r i n g this p e r i o d it was l e a r n e d that cholesterol, first d i s c o v e r e d

(10)

i n 1812 a n d c h a r a c t e r i z e d s t r u c t u r a l l y i n 1932, is a c t u a l l y the b i o g e n e t i c r a w m a t e r i a l for a l l of the steroid h o r m o n e s ; i n t u r n , it is p r e c e d e d b i o g e n e t i c a l l y b y the i s o p r e n o i d — s q u a l e n e — a fact w h i c h was suggested as a p o s s i b i l i t y l o n g before the structure of cholesterol b e c a m e k n o w n .

Ex-

cept f o r cholesterol a n d the b i l e acids these substances are of p l a n t o r i g i n , so that the subject of d r u g d i s c o v e r y f r o m a n i m a l sources d i v o r c e d e n t i r e l y f r o m p l a n t sources.

cannot

be

O f the m a i n steroid classifications

o n l y the c a r d i a c glycosides are not represented.

Although medically

i m p o r t a n t , the latter are of p l a n t o r i g i n a n d have not b e c o m e m e a n i n g f u l to steroid h o r m o n e research.

A l l of the steroid substances s h o w n i n this

table have b e e n or n o w are i m p o r t a n t r a w materials u s e d to m a n u f a c t u r e steroid h o r m o n e s .

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

HOGG

Animal

19

Sources

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Table IV.

Available D r u g Entities

Corticosteroids

Progestins

Betamethasone Cortisone Desoxycorticosterone Dexamethasone Fludrocortisone Fluprednisolone Hydrocortisone Methylprednisolone Paramethasone Prednisolone Prednisone Triamcinolone

Dydrogesterone (Duphaston) Ethisterone (Pranone) Hydroxyprogesterone (Prodox) Medroxyprogesterone (Provera) Norethindrone (Norlutin) Progesterone Contraceptives C h l o r m a d i n o n e -f- m e s t r a n o l (C-Quens) D i m e t h i s t e r o n e -f- e t h i n y l estradiol (Oracon) E t h y n o d i o l + mestranol (Ovulen) Medroxyprogesterone + ethinyl estradiol (Provest) Norethindrone + ethinyl estradiol (Norlestrin) Norethindrone + mestranol ( Ortho-No vum) Norethynodrel + mestranol (Enovid-E)

Androgenic

Agents

Topical A.LF. Agents Dichlorisone (Diloderm) Flurandrenolide (Cordran) Fluocinolone (Synalar) Fluorometholone (Oxylone) Hydrocortamate (Magnacort) Anabolic

Agents

Ethylestrenol (Maxibolen) Methandrostenolone (Dianabol) Nandrolone (Durabolin) Norethandrolone (Nilevar) Oxandrolone (Anavar) Oxymetholone (Adroyd) Stanazolol (Winstrol)

Estrogens

Fluoxymesterone (Halotestin) Methyltestosterone Stanolone ( N e o d r o l ) Testosterone

Estradiol Estriol Estrone E t h i n y l estradiol

Miscellaneous D e h y d r o c h o l i c a c i d (choleretic) D i g i t a l i s (cardiotonic ( m i x t u r e of steroid glycosides)) D i h y d r o t a c h y s t e r o l ( t r e a t m e n t of h y p o p a r a t h y r o i d i s m ) Dromostanolone (2a-methylandrostan-170-ol-3-one, 17-propionate b o l i c - a n d r o g e n i c , for cancer o n l y ) H y d r o x y d i o n e ( V i a d r i l ) (anesthetic) Pregnenolone (listed i n M o d e l l , use u n k n o w n ) Medrysone (ophthalmic) Sitosterols (antihypercholesterolemic) V i t a m i n D (Calciferol) (vitamin)

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

(ana-

20

DRUG

The

120-year-long

investigation on

the

structure

of

DISCOVERY

cholesterol,

m a r k e d e s p e c i a l l y b y the b r i l l i a n t research of W i n d a u s a n d W i e l a n d i n the e a r l y 1900s, s u c c e e d e d i n 1932.

T h i s k n o w l e d g e w a s the k e y to the

structures of a l l steroid classes u n d e r i n v e s t i g a t i o n , i n c l u d i n g the steroid h o r m o n e s , w h i c h q u i c k l y f e l l i n p l a c e . W h e r e a s the b i r t h of t h e s t e r o i d h o r m o n e era has b e e n a t t r i b u t e d to the 1930-40 p e r i o d , w e see that this p e r i o d m a r k s i n s t e a d the m a t u r a t i o n of the steroid field as a w h o l e . C o n ­ s i d e r a t i o n of the events before 1930, therefore, c a n not be e x c l u d e d i n s e a r c h i n g f o r significant factors i n u n d e r s t a n d i n g the process of

drug

Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

d i s c o v e r y f r o m n a t u r a l sources a n d i n p a r t i c u l a r steroid h o r m o n e s . T h e r e is some m e r i t i n t h i n k i n g of the p r e - s t e r o i d h o r m o n e era as the subconscious phase of s t e r o i d h o r m o n e research, the results of w h i c h later p r o v i d e d goals c l e a r l y r e l a t i n g to d r u g p o t e n t i a l . E a r l y research i n the separate s t e r o i d categories i n T a b l e V w e r e c o n d u c t e d w i t h o u t k n o w l ­ edge of the s t r u c t u r a l s i m i l a r i t y that existed b e t w e e n t h e i r H o w e v e r , t h r o u g h o u t these w i d e l y separated relationships w e r e established.

members.

studies n u m e r o u s

inter­

F o r e x a m p l e , i n 1919 the c o n v e r s i o n of

cholesterol to c h o l a n i c a c i d s h o w e d for the first t i m e that these t w o major categories are b o t h s t e r o i d a l . T h e established facts of e a c h series a c c u m u l a t e d over a c e n t u r y n o w b e c a m e a p p l i c a b l e to the other. T h e l o n g p e r i o d s of t i m e r e q u i r e d f o r these e a r l y d e v e l o p m e n t s h a v e no r e l a t i o n to the a v a i l a b i l i t y of the n a t u r a l s t e r o i d substances t h e y w e r e a b u n d a n t l y a v a i l a b l e f o r research purposes. contrast

to the

a v a i l a b i l i t y of steroid h o r m o n e

because

T h i s is i n sharp

substances

discussed

earlier. H o w e v e r , the entire science of o r g a n i c c h e m i s t r y w a s e m e r g i n g d u r i n g this p e r i o d so that the rate of progress i n steroid reseach

kept

p a c e w i t h the d e v e l o p i n g g e n e r a l m e t h o d o l o g y . Table V .

Precursors of Steroid Hormones (Timetable of Discovery) Steroid Hormone 1800 1 1

Sterols (hundreds) Cholesterol Ergosterol

15

30

45

60

75

90

1 I

1 I

1 ι

1 1

1 1

1 1

Sapogenins (40 ± ) Diosgenin

Cortisone Era

I

i

35

50 1 1

1 1

;â)

(2) (2)

(Î) (Î)

(20)

Cholicacid

α

2C

1 !

(i)

Stigmasterol Bile Acids

1905

Era

(2) (Î)

(2) ( i s o l a t i o n of gitogenin)

(i)

(2)

Legend: (1) isolation, (2) structure, (3) configuration.

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

Animal

HOGG

Table V I .

Instrumental and Analytical Techniques Applied Steroid Research (Timetable) Application to Steroids

Instrument Ultraviolet absorption

1930

Paper chromatography I n f r a r e d spectrometry R o t a t o r y dispersion

e a r l y 1950's 1955

N u c l e a r magnetic resonance Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

21

Sources

X - r a y diffraction M a s s spectrometry Gas chromatography

1949

1958 late 1950's 1 9 5 8 - 59 1 9 5 9 - 60

to

Comment Beckman D U a v a i l a b l e 1940 by Zaffaroni Commercial instrument same y e a r Commercial instrument i n 1955-56

Instrumentation i n 1951-52

T h e entire p e r i o d , e s p e c i a l l y as w e a p p r o a c h the s t e r o i d h o r m o n e era, is m a r k e d b y the confluence of n u m e r o u s other lines of endeavor, b o t h c h e m i c a l a n d b i o l o g i c a l , w h i c h c u m u l a t i v e l y r e s u l t e d i n the r a p i d progress f r o m 1930 to 1940.

H o w e v e r , the goals of the i n d i v i d u a l re-

searchers of the t i m e w e r e u s u a l l y t e c h n i c a l i n nature. S ô d e r b a u m

reflects

this o n the o c c a s i o n of the N o b e l lectures of 1928 b y W i n d a u s a n d W i e l a n d w h e n he s a i d that the investigations o n steroids " w e r e a l l d e s i g n e d to e x p l a i n the i n t e r n a l structure of o r g a n i c materials, t h e i r r e l a t i o n s h i p w i t h one another a n d their transitions i n t o one a n o t h e r . " H e c o n t i n u e s : " f o r this reason t h e y are of f u n d a m e n t a l i m p o r t a n c e for o u r k n o w l e d g e of a n u m b e r of processes o c c u r r i n g i n b o t h the h e a l t h y a n d diseased org a n i s m , a n d therefore of greatest significance, not o n l y for the c h e m i s t r y as s u c h , b u t also f o r the sister sciences, p h y s i o l o g y a n d m e d i c i n e " F r o m this it is clear that the scientific c o m m u n i t y , o n the eve of

(II). the

steroid h o r m o n e era, h a d c l e a r l y sensed the p o t e n t i a l i m p o r t a n c e of the developing long

field.

It has also b e e n s a i d that W i n d a u s h e l d this v i e w

before. T h e s p r e a d of steroid research o n a w o r l d - w i d e basis is t y p i c a l of a

p h e n o m e n o n i n research i n w h i c h trends d e v e l o p spontaneously, r e s u l t i n g i n g l o b a l research teams a n d r e m a r k a b l y w e l l b a l a n c e d b u t c o m p e t i t i v e p r o g r a m s . E q u a l l y spontaneous is the a s s u m p t i o n of l e a d e r s h i p i n g u i d i n g s u c h trends; u s u a l l y one c a n i d e n t i f y a f e w pioneers w h o w e r e responsible f o r s h a p i n g the course of the o v e r a l l effort e v e n t h o u g h it is widespread. It w o u l d seem that the early s t e r o i d w o r k n o w stands as a m o d e l of basic research w h i c h i n its entirety p r o v i d e s e v i d e n c e that b a s i c research r e l a t i n g to n a t u r a l p r o d u c t s n e e d not be w i t h o u t p u r p o s e f u l d i r e c t i o n , a n d that p r i v a t e a n d p u b l i c f u n d s , p r o p e r l y a d m i n i s t e r e d i n s u p p o r t of s i m i l a r

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

22

DRUG

DISCOVERY

research, c a n b r i n g r i c h r e w a r d s . It is of interest that at least 10 research pioneers h a v e r e c e i v e d N o b e l p r i z e s f o r t h e i r research i n o r r e l a t e d to the s t e r o i d

field.

B e f o r e l e a v i n g the steroids to take u p the p r o s t a g l a n d i n s , i t is i m p o r tant t o assess t h e i m p a c t of m o d e r n i n s t r u m e n t a l a n d a n a l y t i c a l t e c h n i q u e s o n s t e r o i d h o r m o n e research.

T a b l e V I shows that t h e g e n e r a l use of

these t e c h n i q u e s i n s t e r o i d research b e g a n d u r i n g t h e 1950's, t o o late t o

Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

assist i n t h e s t e r o i d h o r m o n e era. T h e cortisone e r a t h r o u g h t h e 1950's

C00H

C00H C00H

8,11,14-EICOSATRIENOIC ACID

C00H

C00H

5.8.IIJ4-EIC0SATETRAENOIC ACID

C00H

C00H

'C00H

5,8,11,14,17-EICOSAPENTAENOIC ACID

C00H

Figure 2.

The naturally

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

occurring

2.

Animal

HOGG

benefitted

23

Sources

i n c r e a s i n g l y as j u d g e d b y the t i m e t a b l e

steroids s h o w n here.

of a p p l i c a t i o n to

H o w e v e r , as w e shift n o w to t h e e m e r g i n g field of

p r o s t a g l a n d i n research, w e see that several of these d e v e l o p i n g t e c h n i q u e s p r o v i d e d t h e k e y to o p e n i n g u p this

field.

Prostaglandins B i o d e t e c t i o n of t h e substances n o w k n o w n as t h e p r o s t a g l a n d i n s w a s first r e p o r t e d i n 1930 b y K u r z r o k a n d L i e b (12),

Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

0

0

w h o demonstrated

C00H

PGA, 0

OH 19-HYDROXY-PGBi

OH I9-HYDR0XY-PGA 0

0

PGA

PGB

2

0

2

0

υ

π

OH

I9-HYDR0XY-PGA

prostaglandins

υ

and their

"

OH

I9-HYDR0XY-PGB

2

2

precursors

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

24

DRUG

DISCOVERY

that f r e s h h u m a n semen c o u l d cause s t r o n g contractions or r e l e x a t i o n w h e n a p p l i e d to strips of the h u m a n uterus. N o t e that this date c o i n c i d e s w i t h the b e g i n n i n g of the s t e r o i d h o r m o n e era. It is a c u r i o u s c o i n c i d e n c e that i n the A u g u s t 1935 issue of Klinische

Wochenschrift

there a p p e a r e d

o n c o n s e c u t i v e pages the assignment of the n a m e p r o s t a g l a n d i n to this n e w substance b y v o n E u l e r ( 13 ) a n d the assignment of the t e r m progesterone to the n e w l y i s o l a t e d s t e r o i d a l c o r p u s l u t e u m h o r m o n e b y B u t e n a n d t

(14).

T h a t b o t h substances s h o u l d e v e n t u a l l y p r o m i s e means of p o p u l a t i o n c o n t r o l is e v e n m o r e i n t r i g u i n g . Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

F i g u r e 2 shows structures for the entire p r o s t a g l a n d i n f a m i l y .

The

s e c o n d c o l u m n shows the six p r i m a r y p r o s t a g l a n d i n s , so d e s i g n a t e d because i n t h e i r biogenesis none are precursors of the other.

T h e prosta-

g l a n d i n s m a y be d e f i n e d as l i p i d - l i k e , l o c a l h o r m o n e s , present i n n u m e r o u s m a m m a l i a n tissues. A m u s i n g b u t s u p e r f i c i a l analogies to the steroids are t h e c y c l o p e n t a n e r i n g , the 20 c a r b o n atoms, a n d the presence or absence of a n h y d r o x y l g r o u p at p o s i t i o n 11. M o r e m e a n i n g f u l is t h e i r f o r m a t i o n b i o g e n e t i c a l l y f r o m the essential p o l y u n s a t u r a t e d acids b y e n z y m e cata l y z e d c y c l i z a t i o n as s h o w n i n this squalene as p r e c u r s o r to cholesterol.

figure

(15),

a s t r i k i n g a n a l o g y to

T h e f a t t y a c i d precursors of the

p r o s t a g l a n d i n s are counterparts of the steroids of the p r e - h o r m o n e era, b u t the vast f a t t y a c i d t e c h n o l o g y d i d not m a t c h the steroid c o u n t e r p a r t i n c o n t r i b u t i n g later to the r a p i d d e v e l o p m e n t of p r o s t a g l a n d i n s , e x c e p t i n g t h e i r use as b i o s y n t h e t i c r a w m a t e r i a l . T a b l e V I I shows a p a r t i a l list of d e m o n s t r a t e d occurrences i n m a m m a l i a n tissues f o r the six p r i m a r y p r o s t a g l a n d i n s . I n the early years the facts that the p r o s t a g l a n d i n s are u b i q u i t o u s i n t h e i r d i s t r i b u t i o n , are r a p i d l y m e t a b o l i z e d , are not c i r c u l a t i n g hormones, a n d e l i c i t m u l t i p l e b i o l o g i c a l responses l e d some to argue that t h e y w o u l d never h a v e u s e f u l m e d i c i n a l properties.

O t h e r s i n t e r p r e t e d these facts i n just the opposite

way. T a b l e V I I I shows that the c o n c e n t r a t i o n of PGEi e q u i v a l e n t s i n several sources is v e r y s m a l l , a fact w h i c h accounts greatly f o r t h e del a y e d d e v e l o p m e n t of the p r o s t a g l a n d i n s . T h e s p e c i a l p r o b l e m of collecti n g large q u a n t i t i e s of some of these substances richest i n p r o s t a g l a n d i n s is o b v i o u s .

S h e e p v e s i c u l a r glands e v e n t u a l l y p r o v e d to b e the

p r a c t i c a l source.

most

T h e prostaglandin discovery a n d development time-

table s h o w n i n T a b l e I X , w h e n compared w i t h the steroid timetables, reveals some of t h e differences

as w e l l as s i m i l a r i t i e s b e t w e e n

these

developments. T h e p r o s t a g l a n d i n era b e g a n w i t h its b i o d e t e c t i o n b y K u r z r o k

(12)

i n 1930 i n h u m a n semen, w h i c h w a s s h o w n to contract or relax strips of h u m a n uterus. F o r the next 29 years p r o s t a g l a n d i n research m o v e d at a s l o w pace, a v e r a g i n g one p u b l i c a t i o n p e r year, w h i l e s t e r o i d h o r m o n e

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

HOGG

Animal

Table VII. Source

Occurrence of Prostaglandins PGE,

PGE

PGE

PGF

+ + +

+ +

+ +

+ +

V e s i c u l a r g l a n d , sheep Seminal plasma, human sheep M e n s t r u a l fluid L u n g s , sheep

Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

25

Sources

Pig. bovine guinea p i g monkey man I r i s , sheep B r a i n , bovine cat T h y m u s , calf Pancreas, bovine A d r e n a l , cat Fat, rat K i d n e y , rabbit Intestine, frog S p i n a l c o r d , frog

2

la

PGF

+ +

+

+

+ + +

Table VIII.

3

+

+

PGF

2a

S

+ + + + + + + + + +

+

+

+

Concentration of Prostaglandins

Tissue

PGE

Sheep v e s i c u l a r g l a n d H u m a n semen Cat thymus D o g s p i n a l cord

10-500 /xgram/gram 2 5 - 7 8 0 /^gram/ml 0.8 /xgram/gram 104 ttgram/gram

Sheep l u n g H u m a n lung

0.5 /xgram/gram 0.02 /xgram/gram

t

Equivalent

PGF

2a

research m a t u r e d a n d r e a c h e d its p e a k d u r i n g the same p e r i o d of t i m e . T h e s e e a r l y p u b l i c a t i o n s e m a n a t e d l a r g e l y f r o m a f e w laboratories:

von

E u l e r i n Sweden, Goldblatt i n England, and Bergstrom i n Sweden.

This

is i n sharp contrast to the effort o n steroid h o r m o n e a n d

pre-hormone

steroids, w h i c h o c c u r r e d i n m a n y laboratories a r o u n d the w o r l d .

Even

t h o u g h W i n d a u s has

other

been

c a l l e d the f a t h e r of steroids,

many

pioneers are r e c o g n i z e d . P r o b a b l y the most significant factor i n the s l o w p a c e d u r i n g the e a r l y years ( 1930-1956 ) w a s the scarcity of the n a t u r a l l y o c c u r r i n g m a terials w h i c h c o n t a i n e d o n l y l o w levels of the active substances.

When

B e r g s t r o m of the K a r o l i n s k a Institute, w h o likes to "isolate t h i n g s , " c a m e b a c k to the p r o b l e m i n 1956-57, he b r o u g h t w i t h h i m a vast

experience

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

26

DRUG

DISCOVERY

w i t h nature's a c i d i c substances, the b i l e acids, a n d essential f a t t y acids, fields

i n w h i c h he w a s a l r e a d y p r o m i n e n t .

This background was

an

i m p o r t a n t a d j u n c t to the task at h a n d a n d p r o b a b l y e n h a n c e d t h e f a s c i n a t i o n f o r i s o l a t i n g this u n k n o w n a c i d i c l i p i d - l i k e substance c a l l e d prostaglandin. T w o i m p o r t a n t d i f f e r e n t i a l t e c h n o l o g i c a l factors contrasted the r e a l b e g i n n i n g of the p r o s t a g l a n d i n era i n 1956 a n d the steroid h o r m o n e era of the 1930's.

O n e of these is the m a t u r a t i o n of m o d e r n i n s t r u m e n t a l

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Table IX.

1930

First Clue

34

38

The Prostaglandins—Discovery

4%

46

Early Characterization (16-19)

Prostaglandin

50

Interim A c t i v i t y (20)

K,

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

HOGG

Animal

27

Sources

a n d a n a l y t i c a l t e c h n i q u e s , w h i c h a r r i v e d too late to h e l p i n the s t e r o i d hormone breakthroughs.

G a s c h r o m a t o g r a p h y , mass s p e c t r o m e t r y , a n d

u l t r a m i c r o a n a l y t i c a l t e c h n i q u e s w e r e a p p l i e d i n a series of b r i l l i a n t i n vestigations f r o m w h i c h the structure (23,

24)

of PGEi ( 1 9 6 2 ) as w e l l

as the w h o l e f a m i l y of n e w p r o s t a g l a n d i n substances e m e r g e d ( b y 1966 ). I s o l a t i o n w a s g u i d e d b y the s m o o t h m u s c l e strip assay.

T h e s e achieve-

ments s t a n d as the classic e x a m p l e of the first structure e l u c i d a t i o n of a

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and Development (Timetable) 54

62

66

70

I

I

I

74

Future

Clinical

Isolation (21,22) « S t r u c t u r e (23, 24)

Biology

Biosynthesis (25-27)

Metabolism (28)

Analogs

Total Synthesis (29-32)

j

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

28

DRUG

DISCOVERY

f a m i l y of n e w a n d i m p o r t a n t n a t u r a l p r o d u c t s u t i l i z i n g a d v a n c e d i n s t r u m e n t a t i o n , e s p e c i a l l y mass spectrometry. T h e other i m p o r t a n t difference f r o m the steroid hormones

is t h e

c o m p l e t e absence of awareness of t i e - i n w i t h investigations a l o n g other lines o f n a t u r a l p r o d u c t research p r i o r to t h e structure w h i c h w e r e therefore essentially de novo.

determinations,

H o w e v e r , after t h e structures

b e c a m e k n o w n , three different laboratories ( 2 5 - 2 7 ) i n d e p e n d e n t l y recogn i z e d t h e p o s s i b i l i t y of t h e C » u n s a t u r a t e d fatty acids as b i o s y n t h e t i c 0

precursors ( F i g u r e 2 ) . T h u s the essential fatty a c i d t e c h n o l o g y b e c a m e Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

u s e f u l to t h e p r o s t a g l a n d i n effort b u t at a later p o i n t o n t h e t i m e t a b l e — n a m e l y as r e a d i l y a v a i l a b l e s t a r t i n g m a t e r i a l f o r e n z y m a t i c i n tissue homogenates

to t h e p r o s t a g l a n d i n s .

d u c e d i n this m a n n e r t h e b i o l o g i c a l phase

conversion

W i t h prostaglandins proof p r o s t a g l a n d i n s

became

possible. T h e U p j o h n C o . w h i c h h o l d s a basic U . S . patent to this process ( 2 7 ) , p r o v i d e d h u n d r e d s of laboratories w i t h research quantities of the prostaglandins. I n d u s t r i a l c o l l a b o r a t i o n w i t h a c a d e m i c institutions w a s characteristic d u r i n g the s t e r o i d d e v e l o p m e n t s .

T h e same is also true f o r the prosta-

g l a n d i n s . P r i o r to the K a r o l i n s k a assault o n the p r o s t a g l a n d i n structure, 1200

1100

1000

1930

Figure 3.

1940

1950

1960

Accumulated publications taglandins

1970

on pros-

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

HOGG

David

Animal

29

Sources

Weisblat arranged for T h e

U p j o h n C o . to assist the

project

t h r o u g h s u p p o r t for c o l l e c t i n g large quantities of sheep s e m i n a l v e s i c u l a r g l a n d s ; this c o l l a b o r a t i o n , i n v o l v i n g a n exchange of materials a n d tech­ n o l o g y , has c o n t i n u e d .

Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

Table X .

Areas of Potentials Use for Prostaglandins

M u l t i p l e smooth muscle properties Intermediary metabolism P h y s i o l o g y of the c e n t r a l nervous s y s t e m Gastrointestinal physiology Cardiovascular physiology Reproductive physiology W i t h the p r o s t a g l a n d i n structures k n o w n , the goal for t o t a l synthesis was established.

S u c h studies b e g a n i n several laboratories l o n g b e f o r e

clear e v i d e n c e of t h e r a p e u t i c p o t e n t i a l was established.

T h e first s y n ­

thesis of a p r o s t a n o i c a c i d , one of the metabolites of p r o s t a g l a n d i n E was r e p o r t e d ( 2 9 )

i n 1966.

1 ?

Since then the t o t a l synthesis of a l l of the

p r i m a r y p r o s t a g l a n d i n s has b e e n r e p o r t e d (30-32).

These developments,

c o u p l e d w i t h the b i o s y n t h e t i c techniques, p r o v i d e d t e c h n o l o g y for a n a l o g synthesis, a n a c t i v i t y w h i c h also p r e c e d e d established t h e r a p e u t i c p o t e n ­ tial.

S e v e r a l analogs p r e p a r e d b y the b i o s y n t h e t i c route h a v e b e e n re­

ported.

I n our laboratories several h u n d r e d analogs a n d isomers

have

b e e n s y n t h e s i z e d , a n e n d e a v o r b a s e d o n the c o n v i c t i o n that the prosta­ g l a n d i n s w o u l d e v e n t u a l l y p l a y a n i m p o r t a n t role i n t h e r a p y . T h e u p s u r g e of interest i n p r o s t a g l a n d i n research

is d r a m a t i c a l l y

r e v e a l e d i n F i g u r e 3 w h i c h shows the n u m b e r of p u b l i c a t i o n s against t i m e . T h e a s y m p t o t i c increase i n p u b l i c a t i o n s f r o m 1965 to 1970 the r e n e w e d interest i n b i o l o g y m a d e possible b y the generous

reflects

aforementioned

d i s t r i b u t i o n of b i o s y n t h e t i c p r o s t a g l a n d i n s for b i o l o g i c a l re­

search. T h e c l i n i c a l phase of p r o s t a g l a n d i n research is n o w w e l l a d v a n c e d i n the U n i t e d States a n d a b r o a d . T a b l e X s u m m a r i z e s some of the areas of b i o l o g i c a l a n d m e d i c a l interest.

T h e c l i n i c a l efficacy of PGEo a n d

P G F « i n a b o r t i o n a n d l a b o r i n d u c t i o n has b e e n established. 2

Clinical

studies i n c a r d i o v a s c u l a r disease a n d as gastric antisecretory agents are also i n progress.

T h e a l l e v i a t i o n of the s y m p t o m s of a s t h m a i n h u m a n s

w i t h the Ε p r o s t a g l a n d i n s has b e e n r e p o r t e d

(34).

T h e genèses of d r u g d e v e l o p m e n t s , i l l u s t r a t e d s p e c i f i c a l l y b y

the

steroid hormones a n d p r o s t a g l a n d i n s , are n u r t u r e d b y the d e v e l o p m e n t s i n the b a s i c sciences a n d are often extensions of research a i m e d at other goals. P r o b a b l y the greatest single factor i n p a c i n g the rate of d i s c o v e r y a n d d e v e l o p m e n t of n e w fields is the a v a i l a b i l i t y of a d e q u a t e t e c h n o l o g y .

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

30

DRUG

DISCOVERY

Patterns of d r u g d e v e l o p m e n t are o b v i o u s f o r b o t h fields discussed. T h e s e patterns are variations of the order i n w h i c h the k e y stages o n the t i m e t a b l e occur. N o t o b v i o u s is the f o r m u l a for i n i t i a t i v e . W h e r e a s integ r a t e d w o r l d w i d e trends i n v o l v i n g g l o b a l research teams e v o l v e as gene r a l awareness i n a n y g i v e n field increases, the b r e a k t h r o u g h s into t r u l y v i r g i n t e r r i t o r y come f r o m those v e r y f e w leaders w i t h i n t u i t i o n a n d

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insight.

24-METHYLENECHOLESTEROL

CHOLESTEROL

COOH

•COOH

3«, 7«, 12—TRIHYDROXY-25COPROSTANIC ACID (25« AND 25/3 FROM FROG BILE; 25- FROM CROCODILE BILE)

CHOLIC ACID

COOH

H

OH 15-EPI PGA

PGA,

2

(ACETATE, METHYL ESTER)

Figure 4.

Evolutionary

variation in chemical species

T h e r e c o r d of the past a n d the h i g h p r o m i s e i n c u r r e n t l y e m e r g i n g n e w fields of n a t u r a l p r o d u c t s of a n i m a l o r i g i n attest to the p o t e n t i a l f o r the f u t u r e i n this

field.

T h e p r o b a b i l i t y for f u t u r e d i s c o v e r y of e n t i r e l y

n e w classes of substances of a n i m a l o r i g i n cannot without breakthroughs

be guessed.

i n t o n e w areas, several a c t i v e

fields

of

Even today

p r o m i s e c o n t e m p o r a r y b r e a k t h r o u g h s w h i c h w i l l b e c o m e the h i s t o r i c a l

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2.

HOGG

Animal

31

Sources

accounts o f t o m o r r o w s success stories—e.g., t h e p e p t i d e h o r m o n e

field

w h e r e i n progress has k e p t p a c e w i t h e m e r g i n g t e c h n o l o g y . H o w e v e r , substances of a n i m a l o r i g i n w h i c h serve to regulate b o d y f u n c t i o n h a v e u n i q u e p o t e n t i a l f o r t h e r a p e u t i c usefulness r e l a t i v e t o other substances o f n a t u r a l o r i g i n .

B e r g m a n n i n h i s r e v i e w ( 3 5 ) o f t h e evo­

l u t i o n a r y aspects of sterols o b s e r v e d that cholesterol, t h e d o m i n a n t sterol p r o d u c e d i n h i g h e r forms of a n i m a l l i f e , h a d n u m e r o u s c h e m i c a l l y r e l a t e d c o m p a n i o n s i n l o w e r forms of l i f e , o n e of w h i c h is 2,4-methylene

cho­

lesterol. E v e n t h e b i l e acids a p p e a r i n different s t r u c t u r a l m o d i f i c a t i o n s Downloaded by UNIV QUEENSLAND on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch002

i n l o w e r forms o f l i f e s u c h as t h e f r o g a n d c r o c o d i l e . B e r g m a n n defines the e m e r g e n c e o f cholesterol as t h e d o m i n a n t sterol i n h i g h e r a n i m a l s as a " p h e n o m e n o n of b i o - c h e m i c a l e v o l u t i o n " a n d c o n c l u d e s that " I t w o u l d a p p e a r that i n cholesterol w e witness t h e s u r v i v a l of t h e fittest s t e r o l . " A l r e a d y i n t h e n e w field o f p r o s t a g l a n d i n s w e h a v e a n e x a m p l e i n P. Homomalla,

a g o r g o n i a n of t h e c o r a l reefs a n d a l o w e r f o r m o f a n i m a l

life, w h i c h p r o d u c e s a p r o s t a g l a n d i n substance (36). differs f r o m P G A

2

This prostaglandin

o n l y i n t h e stereochemistry at carbon-15.

It is reasonable

( Figure 4)

to c o n c l u d e that t h e p e r p e t u a t i o n of r e g u l a t o r y

c h e m i c a l species o r their precursors as p r o d u c t s of m a m m a l i a n b i o c h e m ­ istry is a result of t h e s u r v i v a l v a l u e they h a v e c o n t r i b u t e d to t h e o r g a n i s m they serve, a n d therefore s u c h substances w i l l i n some w a y d i r e c t l y o r i n d i r e c t l y b e f o u n d to p l a y a role i n h u m a n m e d i c i n e .

Literature Cited (1) (2) (3) (4) (5) (6) (7) (8) (9)

Allen, E., Doisy, Ε. Α., J. Amer. Med. Assoc. (1923) 81, 819. Corner, G. W., Allen, W. M., Amer. J. Physiol. (1928) 86, 74. Fieser, L. F., Fieser, M., "Steroids," p. 503, Reinhold, New York, 1959. Ingle, D. J., Amer. J. Physiol. (1936) 622. Fieser, L. F., Fieser, M., op. cit., p. 673. Fried, J., Sabo, Emily F., J. Amer. Chem. Soc. (1954) 76, 1455. Cook, J. W., Dodds, E. C., Hewett, C. L., Nature (1937) 131, 56. Feiser, L. F., Fieser, M., op. cit., p. iii. Applezweig, Norman, "Steroid Drugs," p. 88, McGraw-Hill, New York, 1962. (10) Fieser, L. F., Fieser, M., op. cit., p. 3. (11) Söderbaum, H. G., presentation of Nobel prize in chemistry to Wieland and Windaus, in "Nobel Lectures in Chemistry, 1922-1941," p. 89, Elsevier, Amsterdam, 1966. (12) Kurzrok, R., Lieb, C.C.,Proc. Soc. Exptl. Biol. Med. (1930) 28, 268. (13) von Euler, U. S., Klin. Wochenschr. (1935) 14, 1182. (14) Allen, W. M., Butenandt, Α., Corner, G. W., Slotta, Κ. H., Ibid. (15) Bergström, S., Carlson, L. Α., Weeks, J. R., "The Prostaglandins, a Family of Biologically Active Lipids,"Pharmacol.Rev. (1968) 20 (1), 1-48. (16) Goldblatt, M. W., Chem. Ind. (London) (1933) 52, 1056. (17) Goldblatt, M. W., J. Physiol. (London) (1935) 84, 208. (18) von Euler, U. S., Arch. Exp. Pathol. Pharmakol. (1934) 175, 78. (19) von Euler, U. S., J. Physiol. (London) (1937) 88, 213. (20)Bergström,S., Nord. Med. (1949) 42, 1465.

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32

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(21) Bergström, S., Sjövall, J., Acta Chem. Scand. (1957) 11, 1086. (22) Ibid., (1960) 14, 1693, 1701. (23) Bergström, S., Ryhage, R., Samuelsson, B., Sjövall, J., Acta Chem. Scand. (1962) 16, 501. (24) Bergström, S., Ryhage, R., Samuelsson, B., Sjövall, J., J. Biol. Chem. (1963) 238, 3555. (25) Bergström, S., Danielsson, H., Samuelsson, B., Biophys. Acta (1964) 90, 207. (26) van Dorp, D. Α., Beerthuis, R. K., Nugteren, D. H., Vonkeman, H., Biochim. Biophys. Acta (1964) 90, 204. (27) Beal, P. F. III, Fonken, G. S., Pike, J. E., U.S. Patent 3,296,091 (Jan. 3, 1967). (28) Bergström, S. et al., Pharmacol. Rev. (1968) 20 (1), 4, 30. (29) Beal, P. F. III, Babcock, J. C., Lincoln, F. H., J. Amer. Chem. Soc. (1966) 88, 3131. (30) Axen, U. F., Lincoln, F. H., Thompson, J. L., Chem. Commun. (1969) 303. (31) Just, G., Simonovitch, C., Lincoln, F. H., Schneider, W. P., Axen, U. F., Spero, G. B., Pike, J. E., J. Amer. Chem. Soc. (1969) 91, 5364. (32) Corey, E. J., Andersen, Ν. H., Carlson, R. M., Paust, J., Vedejs, E., Vlattas, I., Winter, R. Ε.K.,J.Amer. Chem. Soc. (1968) 90, 3245. (33) Struijk, C. B., Beerthuis, R. K., van Dorp, D. Α., Nobel Symposium 2, "Prostaglandins," p. 51, S. Bergström, B. Samuelsson, Eds., Almqvist and Wiksell, Stockholm, 1967. (34) Cuthbert, M. F., Brit. Med. J. (1969) 4, 723. (35) Bergmann, W., in "Cholesterol," R. P. Cook, Ed., Chap. 12, Academic, New York, 1958. (36) Weinheimer, A. J., Spraggins, R. L., Tetrahedron Letters (1969) 59, 5185. RECEIVED November 5, 1970.

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.