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2 The Synthetic Penicillins JOHN C. SHEEHAN Massachusetts Institute of Technology, Cambridge 39, Mass.

The semisynthetic penicillins offer an outstanding example of the role chemical modification Downloaded by UNIV OF AUCKLAND on May 3, 2015 | http://pubs.acs.org Publication Date: January 1, 1964 | doi: 10.1021/ba-1964-0045.ch002

can play in improving the medical properties of even a "wonder drug."

Acylation of 6-amino-

penicillanic acid, the "penicillin nucleus," has produced semisynthetic penicillins with demonstrated effectiveness against the troublesome penicillinase-producing

clinically

staphylococcal infections.

resistant

6-Aminopenicillanic

acid can be made by total synthesis or by biochemical techniques, and a chemical method has been devised for interchanging the side chain on the intact nucleus.

The side chain of cepha-

losporin C, a closely related antibiotic, has been removed chemically and acylation of the resulting nucleus (7-aminosporanic acid) yields microbiologically active products. Treatment

of a

penicillin sulfoxide

with

acetic anhydride affords the cephalosporin C ring system, although with different substituents.

Medically useful drugs with a modified

penicillin ring system will probably be found.

T h e semisynthetic penicillins provide one of the best modern examples of how the medical properties of a natural product can be improved by chemical modification of the molecule. Although the discovery of penicillin ushered in a new area of chemotherapy, it has been noted for some years that fermentation-produced penicillins are less than ideal in several major as well as minor respects. Five desirable properties which one might hope to incorporate into a chemically altered penicillin are: 1. 2. 3. 4. 5.

Acid stability Broadened microbiological spectrum Activity against resistant organisms Less allergenicity Greater metabolic efficiency (better oral absorption, slower excretion) 15 In Molecular Modification in Drug Design; Schueler, F.; Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

MOLECULAR MODIFICATION IN DRUG DESIGN

Downloaded by UNIV OF AUCKLAND on May 3, 2015 | http://pubs.acs.org Publication Date: January 1, 1964 | doi: 10.1021/ba-1964-0045.ch002

16

This list was not devised especially for this occasion; it was prepared by this author in 1953. These improved properties have all been observed in the semisynthetic penicillins to a greater or lesser degree, with the possible exception of the lowered allergenicity. In at least one category—activity against penicillin-re sistant organisms (notably penicillinase-producing staphylococci)—the results have been dramatic. According to published clinical reports infections have been successfully treated with at least two of the new penicillins in cases which medical experience and controls indicated would not have yielded to the penicillins produced directly by fermentation. This change from failure to success is an outstanding example of the medical advantages that chemical modification can achieve even in the case of a "wonder drug." In general, three methods can be employed to produce structural variations in the penicillin molecule: addition of precursors to the fermentation media, chemical modification of the fermentation-produced antibiotic or intermediate, and total synthesis. The addition of precursors during the fermentation has thus far been very limited in scope, although the acid-stable penicillin V (phenoxymethylpenieillin) is produced by this method. This review deals principally with chemical alteration of the fermentation-produced antibiotic or intermediate. In Figure 1 penicillin nomenclature is presented (5, 19). A total syn thesis of penicillin V (1957) and a total general synthesis of penicillins (1959) have been reported by Sheehan and Henery-Logan (16, 17, 18). Although total synthesis is the most elegant from an organic chemical point of view, also in principle the most flexible, the numerous steps involved (albeit each proceeds in good yield) render total synthesis noncompetitive industrially with partially synthetic techniques at the present time. 1 RCONH-CH—CH CO—Ν 7

4

C(CH ) 3

CH -CH

2

I

2

I

CO—Ν

CHC0 H 2

C(CH ) I CHC0 H 3

2

2

3

R-Penicillinic acid (5, 19) R-Penicillin (salt)

Penicillanic acid (16, 17, 18) H N 2

H N - C H — CH I I CO—Ν 2

C(CH ) I CHC0 H 3

2

2

fi—N-

-C0 H 2

6-Aminopenicillanic acid

Figure 1. Penicilllin nomenclature One should note particularly the structure of 6-aminopenicillanic acid (6APA), which has been termed the "penicillin nucleus." Our announce ment (13, 14) in March 1958 that ". . . we have prepared this compound [6aminopenicillanic acid (6APA)] via a totally synthetic route . . . We have shown that one can acylate with various acid chlorides and obtain the corresponding penicillins," together with the subsequent development of commercially attrac-

In Molecular Modification in Drug Design; Schueler, F.; Advances in Chemistry; American Chemical Society: Washington, DC, 1964.

2.

SHEEHAN

Synthetic Penicillins

17

tive biochemical routes to 6APA has been followed by the remarkable story of the "semisynthetic" penicillins. In addition to our original totally synthetic route and a chemical partial synthesis from penicillin G (Figure 2), 6APA has been obtained subsequently by direct fermentation and by enzymatic methods from the "natural" penicillins V and G in four independent laboratories (2, 3, 7,9). The semisynthetic penicillins now available commercially are manufactured by one of these biochemical preparations of 6APA followed by the chemical acylation of this key intermediate as first reported by our laboratory. Two independent Japanese laboratories (8, 12) had previously obtained evidence for a penicillin nucleus, but their experiments were not followed up.


g 2

0=C

g ^Ç(CH )

H N-ÇH—ÇH

3

NH—CHC0 CH 2

I OH

(C H ) CC1 6

2

5

'

3

C H ""Ç(CH )

(CeHs^CNH—ÇH

3

3

0=C I OH

2

NH—CHC0 CH 2

3

From total synthesis; and penicillin G |(CH ) CHN=C=NCH(CH ) 3

2

3

S H N-CH-CH 2

0=C

Ν

2

s ^C(CH ) 3

(i) NaOH

2

CHC0 H 2

'

( 2 ) Η 3

°

(C H ) CNH—ÇH—CH 6

5

3

0=C

Θ

^Ç(CH )

1ST

3

2

CHC0 CH 2

6-ΑΡΑ

Figure 2. Total and partial synthesis of 6-aminopenicillanic acid Perhaps the most striking and medically useful change in pharmacological properties of the semisynthetic penicillins as compared with penicillin G is in the 2,6-dialkoxyphenylpenicillin area (6) (Table I ) . For example, 2,6-dimethoxyTable I.

No.

Ri

Methicillin 1 2 3

4 5 6

7

CH C2H5GeHôC6H5CH2C6H5CH2CH2CH CH CH 3

3

3

3

Benzylpenicillin

2,6-DialkoxyphenyIpenicillins

R2 H H H H H 3-C13-CH3O4-CH 03

MIC, μξ./ΜΙ. vs. S. aureus Sensitive Resistant —Serum -{-Serum — Serum +Serum

1.6

1.6

1.6 1.2

>12.5

6.2 3.1 0.8 3.1 3.1 0.05

6.2

>12.5 >12.5 6.2 6.2

>12.5 0.1

3.2 12.5 3.1 3.1 6.2 3.1 3.1 12.5 50


3.2 12.5 100 100 400 6.2 6.2 50 100

3

18


phenylpenicillin (methicillin) has an M I C , micrograms per milliter m. resistant S. aureus, in the clinically useful range of 3.2 (even in the presence of serum), while penicillin G has risen to the medically impractical level of 50 to 100. Another striking change in microbiological properties can be observed in the case of D (—) -α-aminobenzylpenicilhn ( ampicillin ) ( Table II ). The D-epimer is approximately an order of magnitude more effective against certain Gramnegative organisms than is benzylpenicilhn, and the low M I C values indicate that ampicillin should be clinically effective against infections due to these strains. In Figure 3 are listed by name and formula the semisynthetic penicil lins available commercially at the present time.


Penicillin G spectrum 0

f~\

(

"

V-0—CH—C—ΑΡΑ

0

f~\

C(CH C H — Cι H ^ Κ I -Ν C-H

3 2

c-

II I Ο C0 CH These few examples illustrate that properly designed reactions can be carried out on the penicillin nucleus without destruction of the sensitive ^-lac tam, and the development of medically useful compounds by the chemical altera tion of the penicillin ring system can be anticipated. The chemical conversion of the 6APA structure into the 7-cephalosporanic acid system by chemical or biochemical means presents an intriguing scientific challenge. 2


3

SHEEHAN

23

Synthetic Penicillins

0

CH CeH5

C H CH CNH 6

5

CH

2

I

"cH—CH S - C H 3 I

I

C Ο

Ν

2

C^

3

(D^-BuOQ (2) N E t

CHC0 CH 2

Ν \ CH I

3

3

c-

II ο

/

0

CH

CH

-N

3

C-CH

\/

3

I

C0 CH 2

3

|H Pd


2f

N.

C H CH CNH \ CH- -CH 6

5

2

cli

ο

CH

2

-Ν

3

C-CH

3

I

C0 CH 2

3

Figure 8. Opening the thiazolidine ring

Literature Cited

R.

(1) Abraham, Ε. B., Newton, G. G. F., Biochem. J. 79, 377 (1961). (2) Bachelor, F. R., et. al., Nature 1 8 3 , 257 (1959). (3) Claridge, C. Α., Gourevitch, Α., Lein, J., Ibid., 1 8 7 , 237 (1960). (4) Clarke, H . T., Johnson, J. R., Robinson, R., eds., "Chemistry of Penicillin," pp. 239-42, Princeton University Press, Princeton, N. J., 1949. (5) Ibid., p. 1069. (6) Doyle, F. P., Hardy, K., Nayler, J. H. C., Soulai, M. J., Stove, E . R., Waddington, J., J. Chem. Soc. 1 9 6 2 , 1453. (7) Huang, H. T., English, A. R., Seto, T. Α., Shull, G. M., Sobin, Β. Α., J. Am. Chem. Soc.82,3790 (1960). (8) Kato, K., J. Antibiotics(Japan),Ser. A, 6 , 130, 184 (1953). (9) Kaufman, W., Bauer, K., Naturwissenschaften 4 7 , 474 (1960). (10) Morin, R. B., Jackson, B. G., Flynn, E. H . , Roeske, R. W., J. Am. Chem. Soc. 84, 3400 (1962). (11) Morin, R. B., Jackson, B. G., Mueller, R. Α., Lavagnino, E. R., Scanlon, W. B., Andrews, S. L., Ibid., 8 5 , 1896 (1963). (12) Sakaguchi, K., Murao, S., J. Agr. Chem. Soc. Japan23,411 (1950). (13) Sheehan, J. C., "Amino Acids and Peptides with Antimetabolic Activity," G. E . W. Wolstenholme, C. M . O'Connor, eds., p. 258, J. A. Churchill, London, 1958. (14) Sheehan, J. C., Can. Patent 6 1 0 , 0 9 6 (April 25, 1961); U. S. Patent Application, March 1, 1957. (15) Sheehan, J. C., Pure Appl. Chem. 6 , 257 (1963). (16) Sheehan, J. C., Henery-Logan, K. R., J. Am. Chem. Soc. 79, 1262 (1957). (17) Ibid., 8 1 , 5838 (1959). (18) Ibid., 8 4 , 2983 (1962). (19) Sheehan, J. C., Henery-Logan, K. R., Johnson, J. R., Ibid., 7 5 , 3292 (1953). (20) Wolfe, S., Godfrey, J. C., Holdrege, C. T., Perron, Y. G., Ibid., 8 5 , 643 (1963). R E C E I V E D December 9 , 1963.



24

Discussion


L. C . CHENEY,

presiding

Manfred E . Wolff (University of California): I would like to ask Dr. Sheehan concerning the allergenicity of these synthetic penicillins. There was a theory that the allergenicity of penicillin itself is due to the carry-over of the fermentation, some minute amounts of fermentation by-products. Does the allergenicity of the synthetic penicillin have some bearing on this? Dr. Sheehan: Totally synthetic samples of Penicillin G and V from our laboratory have been tested for allergenicity, and they definitely do react in a sensitive patient fully as much as does the material from fermentation. However, what I had in mind was that some of the chemically altered penicillins might be either better tolerated by patients already sensitive, or show less tendency to induce the allergic response in patients who are not al ready sensitive to antibiotics. It is probably too early to say whether this is going to be true. Certain of them do show lowered properties, but I do not think anyone is willing to say that they have been abolished. Dr. Fellano (Ferris State College, Michigan): I notice that in most of your experimental work you worked with an aryl side chain. What is the effectiveness of groups of the alkyl type in the sixth position? Has any work been done in that area? Dr. Sheehan: Yes, both semisynthetic preparations have been prepared. As a matter of fact, the earliest penicillins, originally observed by Fleming, were the aliphatic side chain type, so called Penicillin F and Penicillin K. Peni cillin F had an unsaturated side chain but straight chain, and Κ was fully saturated with eight carbons. Dr. Garrodi Dr. Sheehan, to go back to the subject of allergenicity, may I ask you this: It has been suggested by workers in this country that the haptene, which combines with protein to form the sensitizing compound, is not penicillin itself, but penicillinic acid. If that is true, it should be possible to make a nonallergenie penicillin which does not degrade in that direction. What are your views on the possibility of doing that? Dr. Sheehan: Some of our early totally synthetic penicillins, which were produced as early as 1958, had a side chain which could not produce a peni cillinic acid. That has an unsaturated azlactone structure with a free thiol group. As a matter of fact, the benzylsulfonyl side chain could not produce a benzyl penicillinic acid. I am not sure which of these types have been investigated thoroughly enough to make any comments about the effect. Most of the testing has actually been done on sensitive patients, with patch tests and so forth. But the haptene production would be in the induction of the sensitivity in de novo patients, some one who had not been exposed to penicillin, and at any rate did not have the sensitivity. That is where you would expect it to be effective. I do not know how far these experiments have progressed, although the concept that you did outline does make a great deal of chemical sense.


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