A Key to PHARMACEUTICAL AND MEDICINAL ... - ACS Publications

Antibiotic Literature File for Chemists MARGARET

OHRMUND

The Lilly Research Laboratories, Indianapolis, Ind.

Downloaded by UNIV LAVAL on October 31, 2015 | http://pubs.acs.org Publication Date: January 1, 1956 | doi: 10.1021/ba-1956-0016.ch016

A simple punch-card file has been established to make the current antibiotic literature useful to research personnel engaged in isolation and identification of antibiotics. The coding outline is practical and adapted to the needs of people using the file. A similar file should be useful with the literature of other substances which are not easily classified by the conventional chemical coding system.

V a r i o u s methods are currently available for comparison of new w i t h known antibiotics. Comparison on the basis of antibacterial spectrum lacks specificity. The results of physicochemical tests on the antibiotic samples can be compared, but such a procedure is expensive and not adapted to a large number of samples. Comparison of paper chromatography results is probably the most routinely used method of identification. While this method is generally satisfactory, it too is not foolproof because of the influence of various factors on the location of zones. The fact that actual samples of the known antibiotics must be obtained for comparison is its chief limitation. The antibiotic literature file described i n this paper is an attempt to make the scientific literature useful as a tool for comparison of antibiotics, supplementing the methods mentioned above. Such a file does not permit final identification, but i t helps to narrow down the number of closely related substances. One of its chief advantages is the opportunity for comparison when actual samples are not available. The establishment of the file was justified by the continuing importance of antibiotic research, the great number of antibiotics reported, and the potential prevention of unnecessary laboratory work. The file was originally set up as a name file to supplement Baron's "Handbook of A n t i b i o t i c s " (1). This system was adequate as a collection of information, but, as the file grew, i t became too time-consuming to read each card i n order to compare properties listed with those of laboratory substances. The punched-card system was started so that antibiotics w i t h specific groups of properties could be separated for comparison. Machine-sorted cards were adopted because the equipment was readily available, and the number of punches desired was greater than could be handled on an edge-punched card, using a simple direct code. Coding Outline

The coding outline finally adopted (Table I) was worked out after much consultation with members of the biochemical and microbiological research departments. The primary consideration was usefulness for comparison purposes; many sections of the outline look peculiar when examined from a taxonomic or medical viewpoint. Undoubtedly many people w i l l disagree w!th this arrangement, even for comparison, but agreement is not necessary for use, as long as the user knows what is included in the various sections. The procedure for dealing with the antibiotic salts was one of the most difficult problems i n organizing the physicochemical part of the outline. The free form was selected i n order to have the broadest and most consistent basis for comparison, even though the free form is not often used for biological testing. A simple salt is recorded only when no chemical information can be found for the free form. However, it was undesirable to have sulfates, for example, coinciding with antibiotics containing organic sulfur when the cards were searched, or to have salts coinciding with 143

In A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE; Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

A D V A N C E S IN CHEMISTRY SERIES

144

neutral substances. Therefore exceptions were made as noted i n the sections on ele ments and chemical nature. Table I.

Coding Outline

Physicochemical Data


Outline

Code

No.

Notes

No.

C o l . 0-5

, Chemical purity A . Pure 1. C r y s t a l l i n e B. Impure

Col. 6 11 1 12

. E l e m e n t s ( N o . of A . Carbon 1. 0-10 2. 10-15 3. 15-20 4. 20-25 5. 25-30 6. 30-35 7. 35-40 8. 4 0 + 9. Percentages B. Oxygen 1. 0-8 2. 8-15 3. 1 5 + 4. Percentages C. N i t r o g e n 1. 0-5 2. 5-10 3. 10-15 4. 1 5 + 5. Percentages D . Other 1. S u l f u r 2. C h l o r i n e 3. B r o m i n e 4. Iodine 5. Miscellaneous . M o l e c u l a r weight A. 0-100 B . 100-200 C. 200-300 D . 300-400 E . 400-500 F . 500-600 G. 600-700 H . 700-800 I. 800-900 J . 900-1000 K . 1000+

atoms) Col. 7 1 2 3 4 5 6 7 8 12

0

. Optical rotation A . Water 1. P o s i t i v e 2. N e g a t i v e B. Alcohol 1. P o s i t i v e 2. N e g a t i v e C. C h l o r o f o r m 1. P o s i t i v e 2. N e g a t i v e

I n columns 7-9, code N o . 12 means t h a t a n a l ysis figures f o r element a r e g i v e n b u t N o . of atoms is n o t g i v e n .

Col. 8 1 2 3 12 Col. 9

1 2 3 4 12

C o l . 10 0 1 2 3 4

Elements not punched w h e n a n t i b i o t i c is re ported i n f o r m of salt c o n t a i n i n g t h e m .

E x p e r i m e n t a l , n o t theoretical, values

C o l . 11

reported.

0 1 2 3 4 5 6 7 8 9 11 Blank.

C o l . 12 . Melting., p o i n t A. 0-50 B . 50-100 C. 100-150 D . 150-200 E . 200-250 F . 250-300 G. 300 +

C r y s t a l l i n e substance is considered p u r e . Sub stance is reported as crystalline i f a n y salts are crystalline. N o n c r y s t a l l i n e substance is considered p u r e i f reported p u r e o r 5 0 % + pure.

C. 0 1 2 3 4 5 6

M e l t i n g points of salts not punched unless a n t i b i o t i c is reported i n salt f o r m only.

C o l . 14 11 12 C o l . 15 11 12 C o l . 16 11 12


OHRMUND—ANTIBIOTIC

LITERATURE FILE FOR

CHEMISTS

145

Physicochemical Data


Outline

Code

Col.

V I . Optical spectrum A . 200-220 B . 220-230 C. 230-240 D . 240-250 E . 250-260 F . 260-270 G. 270-280 H . 280-290 I. 290-300 J . 300-320 K . 320-340 L . 340-360 M . 360-380 N . 380-400 O . 400-450 P . 450-500 Q. 500-550 R. 550-600 S. 600-700 T. 700+ V I I . Infrared spectrum V I I I . Chemical nature A. Acidic 1. M o n o - a c i d , 2. M o n o - a c i d , 3. P o l y a c i d i c B. Basic 1. Mono-base, 2. Mono-base, 3. Polybasic C. N e u t r a l D. Amphoteric

No.

17

Notes

A l l m a x i m a reported

0 1 2 3 4 5 6 7 8 9 C o l . 18 0 1 2 3 4 5 6 7 8 9 C o l . 18 12

under a l l conditions.

P u n c h indicates that i n f o r m a t i o n articles cited on master c a r d .

is g i v e n i n

C o l . 19 0

T o be interpreted as " s a l t of a c i d " w h e n salt f o r m of a n t i b i o t i c is coded.

4 5 6

To be interpreted as " s a l t of b a s e " w h e n salt f o r m of a n t i b i o t i c is coded.

pK 5.0 a

a

pK

I II

Ώ V> M

15 36 « 18 39 «0 41

ι ι | π ι ι ι ι ι ι ι ι ι ι ι i|i

1?

43 44 4b 4f, 4? «8

· ||i|i

49

In

50

51

5/ 53 54

55

56

5'

38

59

| i | i | | | i 11 ι

)}

% 6i 6? 63 64 65 66 5; 88 63 70 >i

ι ι ι 11 l l l l .

'3 M

75

76 77

78

79

81

i m

2 2 2 2 2 2 | | | | | 2 | 2 ? 2 | | | | 2 2 | | | | 2 2 2 | 2 2 2 22 2 2 2 2 2 2 2 22 | 2 2 2 2 2 2 2|2 2 2 2 2 22 2 2 2 2 2 2 2 2 2 2 2|||| 2 2 2 2 ? 3 3 3 3 3 3 | | | | | 3 | 3 3 3 | | | | 3 3 3 | | 3 | 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 3 3 3 3 3 3 3 | 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 11111

3 33 3

4 4 4 4 4 ^ | 4 B | | 4 | 4 4 4 | | | | | 4 | | | 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 M 4 4 4 4 4 4 4 4 4 | | 4 4 4 4 4 | | | | 4 4 4 4 4 4 4 4 4 | | | | | 4 4 4 4 5 5 5 5 5 5 | 5 5 5 | 5 | 5 5 5 | | | | | 5 | | | 5 5 5 5 5 5 5 5 5 S 5 5 5 5 5 5 5 5 5 5 | | 5 5 | 5 5 | 5 5 5 | 5 5 5 | 5 5 5 | | | 5 5 5 5 5 5 5 5 | 5 5 5 5 6 6 6 6 6 6 | 6 6 6 | 6 | 6 6 6 | | | 6 6 6 | | | 6 | G 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 S 6 6 6 6 6 6 6 6 | 6 6 6 6 6 6 6 6 6 6 6 6 6 | 6 6 6 6 6 6 6 6 | 6 6 6 6 7 7 7 7 7 7 | 7 7 7 | 7 7-7 7 7 | | |

/ 7 7

/ | | 7 7 7 7 7 7 7'7 M 7 7 M 7 7 M M 7 7 7 7 7 7 7 Ï 7 7 7 7 M | 7 |

7 7 7 7 7 7 7 7 7 7 7 7 7 |7 7 7 7

8 8 8 8 8 8 | 8 8 8 | 8 8 8 8 8 | | | 8 | d | | | 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 3 8 8 | 8 8 8 8 8 8 8 8 d 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 | 9 9 9 9 9 | | | 9 9 9 9 | 9 3 9 9 9 9 9 9 9 9 9 9 Θ 3 9 9 9 9 9 9 9 9 9 9 9 9 9 3 Π 9 9 9 9 9 9 9 9 9 9 9 9 9 | 9 9 9 9 9 9 9 9 Ϊ ) 9 Θ 9 9 I 2 3 4 b C : β 9 10 1112 13 14ttιε :7 :3 in 70 >ι »? 21 '4 25 ' 28 1C il )Γ ).' VI 15 ib H 18 19 «0 41 42 43 «4 45 46 47 48 49 50 51 52 53 54 55 56 5 7 58 M W 61 U 63 * i . 66 6: 58 69 c

Figure 1.

7P

7i

r

Standard IBM card

The possibilities for expansion of the code are indicated both i n the coding out line and i n the card reproduction ( F i g u r e 1). A l l numbers currently being used are punched; the unpunched areas show the space available for expansion. It i s , of course, very difficult to predict just where expansion w i l l be needed. A n effort has been made to leave columns free i n strategic places, and to leave space w i t h i n columns where further subdivision may become desirable. Master Card

Definite information and references supporting the groups punched on the I B M card are contained on the master cards (Figures 2 to 6 ) , which are related to the proper I B M card through the corresponding file number. E a c h card is a different color for quick location i n the files. The "Biological D a t a — i n v i v o " master card is not needed f o r a great many antibiotics. In A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE; Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

73

14 75 76

71

78

79

W


150

III

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 | 0 0 0 0 0 0 0 0 0 0 0 0 ο

1 1 1 1 1

1

1

1

1 1 1 1 '1 111 ! 1 1 1 1 1 1 1 1 11 1 1 1 1

2 2 2 | 2 2 2 ? | 2 2 2 2 2 2 2 2 2 2 2 2 277277 3 3 3 3 3 3 3 3 3 3 3 3 1 3

ηο

ο ο ο υ ο

ο o0

0

Il I ο ο G ο Ι 2 ο ο ο ο ο ο ο ο O|G ο ο ο ο υ : ο ο ο ο ο ο c ο ί ο ο ο ο

1 1 1 1 1 1 1 1 1 1I 1 | l

ι 1 | l

1 1 1 1 1 1 1 I 1 I | l

I444444


7 7 7 7 7 7 ? 7 7 7

2

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4^4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 | 4 4 4 4 4 4 4 4 4 4 4 | 1 | 4 4 4 4 4 4

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 1 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

Π

1112 2 2 2 2

3 3 3 3 i S 3 3 3 3 3 3 33 3 3 3 3 3 3 3 3 3 Π 3 3 33 j 3 3 3 3 3 3 3 3 1 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

4 4 4 4| 4 | 4 4 4 4 4 4 4 4 4 4 4

6 6 6 6 6 6 6 6 6 6 6 6 0 6

1 1 1 1 1 I 1 1 1 » 1 1 1 1 1 1 1 1

2 2 1 ? 2 7 22 2 27 7 777 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

6 6 | b b b G 6 6 6 8 6 6

M 7 7 7 J

G

1555555555555555555555555555

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 S 6 6 6 b 6 6 6 6 6 6 6 6 6 6 6 6 6

/ 7 7 7 7 7 7 7 11111

8 8 8 8 S 8 S 8 8 6 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8

l l l l l l l l l i

Β B

7 / 1 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 ? 7 7 7 7 7 7 7 7 7 7 7 7 7 7 1 7

8 8 6 8 8 8 8 8 8 8 S 8 6 8 8 8 8 8 3 8 8 8 8 8 8 8 8 8 8 8 8 8 8'8 8 3 8 8 8 8 8 8 8 8 8 8 8 8 8

9 9 9 9 9 S 3 9 i 9 9 9 *J 9 3 9 9 9 9 9 9 5 9 9 9 9 9 9 9 3 9 1 9 9 9 0 9 9 9 9 9 3 9 9 3 3 9 9 3 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 3 9 9 9 9 9 9 9 9 9 5 9 9 ι ? ι « ι ·. « is ι· ι. κ

Figure 2.

Name:

Puromycin

"Do n o t p u n c h

where

blanks

L - j

Ho. 24

occur. \o

Ο

Optical Rotation

27

File

ANTIBIOTICS FILE I.Β.M. P u n c h i n g C o d e

_2 C

IBM card

Optical Spectrum

Chemical Color Nature

Solubility

Stability

Qualttativ Tests

28

+

Degradation InactiProducts vating

59

60 61 62

- MycoUfijngiParaIN VITRO s

,65

66 67 68 .

,

t

s

Coding Equivalents!

P.O.I.V.I.P. S.COther Toxicity

Figure 3.

e

Punching code sheet



LITERATURE FILE FOR CHEMISTS

151

ANTIBIOTICS FILE PHYSICOCHEMICAL DATA

CRYSTALS:

Crystilli2ed i n the form of Tarions acid salts and as the free base.

MELTING POINT ι °c >

175.5-177*

(uncorrected)

Porter, J . H .

antibiotics & chemotherapy 2:409-10, 1952.

Waller, C.W.

J . Am. ohem. soc. 75:2025, 1953.

Porter. J . H . Antibiotics & chemotherapy 2:409-10. 1952.

OPTICAL ROTATION:

CHLOROFORM

OPTICAL SPECTfl

Waller, C.W.

J . Am. chem. soc. 75:2025, 1953.

Waller, C.W.

J . Am. chem. soc. 75:2025, 1953.

Porter, J . N . Antibiotics i. chemotherapy 2:409-10. 1952.


ruRE

A diacidic

Waller, C.W. J . Am. chem. soc. 75:2025, 1953.

base.

Porter, J . H . Antibiotics

cher.ot >rapy 2:409-10. V352.

TESTS AND REACTIO

CHEMICAL STRUCTURE AND Group analyses s=ow tne presence of one amino group ('Van DEGRADATION PRODUCTS Slyke), one methox.-l group, two N-methyl groups, and fiv° Waller, C.W. J . Am. chem. soc. 75:225, 19'J3. active hydrogens. Infrared band indicates a carbonyl group. Degradation produotsi '2>Baker, 3.Π. I b i d . , 75:3064-5, 1953. 6-dimethylamino purine, O-methyl-L-tyrosi^, 3-3-aminoribose. 3JBaker, B.3. TÇÏÏ., 76:2β3'3, 195-1. (2) D-3-aminoribose identified by comps-.rison with a synthetic sample. This i s the 4{'Baker, 3.ft. 'Told"., 76:4014-45, 1954. f i r s t known 3-amino sugar and f i r s t known aminopentose to exist i n a natural source. 5)3aker, 3 . H . IbsTracts, ACS 126th meeting, Sept. 12-17, (3) Derivatives: crystalline "aoinonucleoside", 6-dimethylamino-9-(3'-*mino-f>-P1954, c . 13N. ribofuranosylj-purine. A variety of amino acids such as L-phenylalanine, L-tyrosine, (6) Hutchings, B.h. I b i d . , ο. 13*. L-lysine, L-tryptophan, L-leucine, β-alanine, glycine and p-methoxy-L-phenylaianyl(7) Baker, B.fi. J . org7"chem. 19:631-37, *33-45, 645-60, glycine were coupled with the "aminonucleoside* to give analog* of puromycin. 1700-85, 1786-92, 1793-1901, 1954. J4) Total synthesis of puromycin from D-xylose. {5)Structure : 6-dimethylaminû-9-(3'-(p-methoxy-L-phenylalanylamino}-f -D-ribofuxanosylj-purine. ^ (6) Structure:

CH

a

• o -

OGla

(7) Synthetic studies. I . Synthesis of 6-dimethylaminopurine, an hydrolytlc fragment, I I . The position of glycosldation on the 6-dimethylaminopurine moiety. III.Synthesis of 3-aiflino-D-ribose. IV. Glucosyl derivatives of 6-dimethylaminopurine. V . 6-dimethylamino-9-(2 acetafnino-g-D-glueopyranoeyl)-purine. V I . Analogs of 6-dime thylaminopurine. ,

. INACTIVATING AGENTS. A c t i v i t y destroyed by acid hydrolysis. (2) Activity reduced by adenine sulfate i f given to animals i n considerably larger amounts than the a n t i b i o t i c . (3) Various substituted purines reverse the a c t i v i t y of puromycin and an aminonucleoside analog (2484L) against Trypanosoma equlperdurn i n v i v q .

Waller, C.W. J . Am. ohem. soc. 7512025, 1953. '.2)Agosin, M. Antibiotics A chemotherapy 4:624-32, 1954. (3)Hewitt, 3.1. Antibiotics A chemotnerapv 4:1222-27, 1954.

BARON

Figure 4.

KAREL

PRODUCT FILE __X

ABSTRACT FILE

Master card for physicochemical data Upper. Front Lower. Reverse


.


152 NAME Puromyclm SOURCE

FILE NO 24

ANTIBIOTICS F I L E DATA

BIOLOGICAL DATA - λν VITRO

Streptomvces albp-nigcr. n. sp.

REFERENCES

Hesseltine, C.W. Mycologia 46j16-23, 1954.

GRAM POSITIVE

Porter, J . N .

Antibiotics & chemotherapy 2t409-10, 1952.

COCCI Staphylococcus sap., 8. Sarcina lutea. 2 γ/ηΐ. {-HC1)

OTHER

Bacillus spp., 5-β γ/ml. (-KC1)

GRAM NEGATIVE

NON-INDICATIVE

Klebsiella pneumoniae. 5 γ/al. (-AC1)

Porter, J . » .

Antibiotics 4 chemotherapy 21409-10, 1952.

Ο

a:

MYCOBACTERIA


PATHOGENIC FOR MAN

OTHER

OTHER

MEDICAL INTEREST

PARASITES , y/mi, ( 2 ) t ; r i t v of "aminonucleoside" afiainst Trypanosoma équiperai» was increased 3-4 fold over that of puronwnin Itaelf. 1 ) Tetrahymena pyrlformis. T

r

v

p

a

n

o

s

o

m

a

o

r

u

z

i

2

5

A C

3

ORAL LD..o(M^CEI ^ 678 mg/kg. (2)U) (guinea pigs) - 520 mg/kg.

NAME Puromyclm Hewitt, R.I. Am. j . trop. med. 4 hvg. 2:254-^6, 1953. (2)Tavlor, D . J . J . Am. chem. soc. 76:4497, 1954.

eo

INTRAVENOUS LDso (MICE) = 360 mg/kg. , Eviienoe of kidney damage after repeated administration of 25-100 mg/kg. parenterally to rats for frcm 1-4 weeks.

Hewitt,

R.I.

Am. j . trop. med. 4 hyg. 2:254-66, 1953.

Hewitt, R.I. Am. j . trop. med. 4 hyg. 2:254-Λ6, 1953. (2)Antibiotics annual, 1954-55

INTRAPERITONEAL LDso (MICE! 520 mg/kg. ' 2)LD (guinea pigs) - 287 mg/kg. 60

Ο

Hewitt, R.T. A * , J . trop. med. & hvg. 2!254-66, 1953. (2) Baker, B.R. J . An. chem. soc. 76:2038, 1954. (3) Bortle, L. Antibiotics annual, 1954-55

SUBCUTANEOUS LDso (MICE) =

OTHER

LD (guinea S0

Antibiotics annual, 1954-55

pigs) - 202 mg/kg., i.m.

MISCELLANEOUS: Possible mode of action* somewhat inhibits i n v i t r o the overall carbohydrate metabolism of T . eouiperdum. Its aminonueleosTde (an active com ponent) inhibits primarily The 0 consumption and pyruvate production. Effect of adenine sulfate indicates that the k i l l i n g mechanism involves purine metabolism rather than carbohydrate metabolism. (2)Sufigested that the antibiotic i s an antimetabolite of adenine and/or i t s analogs, and affects T . eouiperdum by interfering with purine metabolism and the synthesis sf nucleic acids or nucleoproteins.

Agosin, M. Antibioties & chemotherapy 4:624-32, 1954. {2)Hewitt, R.I. Antibiotics 4 chemotherapy 4:1222-27, 1954.

2

BARON

Figure 5.

: KAREL

PRODUCT F I L E A B S T R A C T FILE

Master card for biological data in vitro Upper. Front Lower. Reverse



LITERATURE

FILE FOR CHEMISTS

153

ANTIBIOTICS FILE BIOLOGICAL DATA - /V ui ROUTE

Heeitt, R.I, ^m. ).

oral, parenteral

trop, med. t t

?:254-*S, 1953.


PATHOGENIC FOR MAN:

MEDICAL INTEREST:

equiperdum i n mice and rabbits, orally and parenterally. T. crazi i n mice, orally and parenterally. ^Toxoplasma gondii i n mice, oraTÎTTprolongation of l i f e ) . (3)Endamoeba histolvtTcîTin guinea pigs, 5.40 rag. free base/kg. body weight. '

Hewitt, R.I, Am. J . trop. med. & hvg. 2:254-*6, 1053. [2) Evles, D. . Antibiotics & chemot'herarv 4:649-52, 1954. [3) Taylor. D . J . J . Am. ehem. soc. 75:449 7, 1954.

TUMOR Appreciable a c t i r i t y found against a glioblastoma cultirated in the embryo and a mammary adeaocarclnoma of the C3H mouse. (2)"Aminon'ieleoside" highly effectire against transplanted mammary adenocarcinoma of C3H mouse,

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