Department of Medical Microbiology, Royal Free and University College Medical School, London, UK
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() |
---|
Notwithstanding the fact that, in earlier decades, manipulation of the penicillin nucleus had failed to produce any novel drugs of interest,2 the second half of the 1970s saw huge progress in useful alterations to the basic penam and cephem ring structures. Penems (Ia) were synthesized,3 naturally occurring carbapenems (Ib, e.g. olivanic acids), oxapenams and monocyclic ß-lactams (nocardicins and monobactams) were discovered,4 ,5 ,6 ,7 and penam sulphones (II) were found to be inhibitors of some ß-lactamases.8 The cephalosporin nucleus was modified to produce microbiologically active oxacephems9 (IIIa) and carbacephems (IIIb).10 Not all changes were advantageous: for example, oxocephems (IV),11 cephams (V)12 and cephems with the double bond in the 2,3 instead of the 3,4 position13,14 had little or no activity.
Many of the active structures mentioned above, as such or after suitable modification, have found their way into clinical practice, for example, imipenem, clavulanate, aztreonam, sulbactam, latamoxef and loracarbef. Many other related compounds have been intensively studied but have either been abandoned as clinical candidates or have not yet been fully developed. Iso-oxacephems (VIa), also reported12 during the fertile period mentioned above, have been reinvestigated recently as possible oral15 or parenteral16 antibiotics. Other similar compounds, synthesized later, also show good antibacterial activity, e.g. isocephems (VIb),17 iso-azacephems18 (VIc) and isopenams (VII).17 penems are still under development as potential therapeutic agents.19
It is the purpose of the present review to draw attention to further chemical modifications, most of them reported recently, to the extremely versatile penam and cephem structures that have sometimes produced surprising pharmacological results.
![]() |
Modifications |
---|
![]() ![]() ![]() ![]() ![]() |
---|
Modest activity against some pathogenic yeasts and filamentous fungi was reported for a cephalosporin whose side chain was an acid (N-benzyldithiocarbamate) having intrinsic antifungal activity.20 Much more intriguing was the finding by the same authors that the aldehyde of penicillin V showed an antifungal action. Another interesting observation that also does not seem to have been studied further, is that unidentified degradation products from aqueous solutions of some first-generation cephalosporins inhibit the growth of certain dermatophytes.21
Compounds with a modified ß-lactam ring
The familiar antimicrobial agents in clinical use either have an unmodified penam or cephem ring, or an alteration has been made in the larger of the two rings (e.g. clavulanate, carbapenems, latamoxef, loracarbef). The four-membered ß-lactam ring (azetidinone) common to both families remains unmodified. Indeed, it has become almost an article of faith that the ß-lactam ring is sacrosanct. However, there have been other preconceptions about this group of antibiotics that have later proved on investigation to be false, e.g. that a monocyclic ß-lactam could never approach the activity of a bicyclic system,22 or that a free carboxyl group is essential.23 Thus this belief must be examined carefully.
Changing the chemical constituents of theß-lactam ring,24 or inserting a 56 double bond in the penam structure (creating a dehydropenicillin (VIII),24,25 not to be confused with an anhydropenicillin (IX)26 in which the elements of water have been removed from the thiazolidine ring) was not a successful strategy to improve antibacterial activity or to inhibit ß-lactamases. On the other hand, increasing the size of the ring from four-membered to five-membered had interesting results.
These interesting properties suggested that analogues of lactivicin might be valuable antibiotics. As a result, the 4-aminolactivicinic acid (4ALA) nucleus (XIb), was synthesized and different side chains were added, following methods perfected for the syntheses of derivatives from the nuclei of the penicillins (6APA), cephalosporins (7ACA) and monobactams (3AMA). The 4ALA analogues of cefotaxime and cephalothin showed high activity against, respectively, Enterobacteriaceae and staphylococci, and orally available prodrugs were also made.30 However, this series was not proceeded with.
An even more radical departure from conventional thinking was made by Imming,31 who synthesized penam analogues in which the ß-ring had been
enlarged to seven or 13 members (the latter sizea -lactamwas considered
optimal).
Chemical but not biological findings are reported.31
Compounds with extra rings
Bridged ß-lactams have an extra ringcreated by cyclization of groups outside the main ring structure(s). These fall into three categories.
(i) Bridged monocyclic compounds. Bridged monobactams (XIIa), sulfactams (XIIb) and other azetidinones, that contain two rings, have been reported to be good inhibitors of class C and, in some cases, class A ß-lactamases.32,33,34
(ii) Bridged penams and carbapenems. The tricyclic 2,3-methylene penams exist in
two
stereoisomeric forms, (XIIIa) and ß (XIIIb). The sulphones of these
compounds show interesting differential properties, the former having good antibacterial activity
and
inhibiting class C ß-lactamases, while the latter are poor antibacterial agents but are inhibitors
of
class A enzymes (penicillinase type).35,36 Thus it seems that the
isomer is recognized by ß-lactamases as a
penem, and the ß isomer as a cephem.
Bridged carbapenems (XIV), in which C1 and C2 are joined through a four-carbon linkage, make up the family of antibiotics given the trivial name tribactams,37 later changed to trinems. Sanfetrinem showed broad-spectrum activity38 and oral availability as a prodrug, but the future of this series is uncertain.
(iii) Bridged cephems and analogues. The first tricyclic cephems, bridged between C2 and C3 (XV), were reported more than 25 years ago.39 They had less antibacterial activity than their corresponding unbridged analogues.
Tricyclic carbacephems (XVIa), with a bridge between C1 and N79, were at first thought to have no useful activity,40 but later derivatives both showed significant antibacterial activity and inhibited class C ß-lactamases.41,42
Bridged iso-oxa (XVIb) and isocephems (XVIc) were found to be better inhibitors of class C ß-lactamases than the bridged monobactams (see above), and furthermore, unlike the monobactams, some (especially the isocephem derivatives) had broad-spectrum antibacterial activity as well.43
Interactions with g-aminobutyric acid (GABA)
Examination of the three-dimensional structures of 3AMA, 6APA, 7ACA and the nocardicin nucleus (3-aminonocardicinic acid) show them to be conformationally rigid analogues of GABA, and as such they act as competitive inhibitors of GABA aminotransferase.44 Inhibition of this enzyme has an anti-convulsive effect.
This relationship is fascinating because ß-lactam antibiotics in current use are known to be capable of having precisely the opposite effecti.e. to cause convulsions. It is suggested that this epileptogenic activity may be due to inhibition of binding of GABA to its receptors.45
Inhibition of human and viral serine proteases
PBPs and many ß-lactamases have a serine motif at their active centres, a property they share with a large class of enzymes known as serine proteases. Several of the latter have been found to be inhibited by certain ß-lactams.
(i) Human leucocyte elastase is inhibited by cephalosporin sulphones.46 The most active compounds had IC50 < 1 mg/L. Inappropriate activity of this enzyme has been implicated in the tissue damage observed in certain chronic conditions, such as cystic fibrosis, rheumatoid arthritis and emphysema. Further studies have identified inhibitors among cephems, penams, penems, monobactams and other related structures.47
(ii) Chymotrypsin and to a lesser extent thrombin were inhibited by some of the sulphone analogues synthesized by Doherty et al.46 (IC50 110 mg/L).
(iii) Protease from cytomegalovirus (assemblin) is inhibited by monocyclic ß-lactams.48 Despite the fact that there is little similarity between herpesvirus proteases and other serine proteases (including ß-lactamases), covalent inactivation of the active site serine in assemblin has been reported.49 This enzyme is important in capsid assembly, so inhibitors may point the way to antiviral agents.
Inhibition of human cytosolic phospholipase A2
This enzyme, thought to be involved with intracellular generation of arachidonic acid, was inhibited by a penam and almost as well by the corresponding penicilloate.50 This suggested that, contrary to the preceding examples, the inhibitory action in this case was due to a mechanism other than the formation with the serine of a covalent acyl intermediate at the active site of the enzyme.
It is interesting that some 20 years previously51 phospholipase A2 from Crotalus adamanteus had been reported to be inhibited by two penams (oxacillin and carbenicillin).
Inhibition of HIV protease
Benzylpenicillin was the starting point for the synthesis of a series of compounds with great inhibitory activity against HIV protease (an aspartate protease). The most active member had an ED50 in a syncytium formation assay of 50 nM. Unfortunately, none of the compounds had satisfactory pharmacokinetic properties, and this line of research has been terminated.52
Delivery of anticancer drugs
Advantage can be taken of the unique way in which many cephalosporins fragment when their ß-lactam ring is broken, namely ejection of their substituent at C3. Attention has been drawn previously53 to the exploitation of this mechanism in dual action antibiotics: here, a new antibacterial compound is produced if the original is attacked by a ß-lactamase. Examples are cephalosporin MCO (which releases pyrothione, an antiseptic) and the cephalosporin/fluoroquinolone hybrids synthesized by Roche, which act as cephalosporins until hydrolysed, when a fluoroquinolone is released.
This process has now been taken a stage further in the design of targeted anticancer prodrugs.54 The strategy is as follows: a conjugate of ß-lactamase with a monoclonal antibody specific for tumour-associated antigens binds to malignant cells. Then a prodrug consisting of an adduct of doxorubicin, a vinca alkaloid or a nitrogen mustard with a cephalosporina covalent bond having been made at the C3 positionis administered. The prodrug is activated only at the surface of the tumour, where the ß-lactamase is bound: breaking the ß-lactam bond causes ejection of the free cytotoxic drug. The advantage of this procedure is that the anticancer agent is much less toxic as a prodrug, so systemic toxicity is reduced.
Reduction in overall toxicity of an anticancer agent has also been reported by the reaction of a retinoid with an isocephem, via an amide linkage at the C4 position.17 It is of interest that the isocephem, which had the same side chain as benzylpenicillin, was highly microbiologically active, although its retinoid conjugate was not.
![]() |
Conclusions |
---|
![]() ![]() ![]() ![]() ![]() |
---|
|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() |
---|
2 . Hamilton-Miller, J. M. T. (1967). Chemical manipulations of the penicillin nucleus: a review. Chemotherapia 12, 7388.
3 . Woodward, R. B. (1976). In Recent Advances in the Chemistry of Beta-Lactam Antibiotics. (Elks J., ed.), pp. 16780. London: Royal Society of Chemistry, London, UK.
4 . Brown, A. G., Butterworth, D., Cole, M., Hanscomb, G., Hood, J. D., Reading, C. et al. (1976). Naturally-occurring ß-lactamase inhibitors with antibacterial activity. Journal of Antibiotics 29, 6689.[ISI][Medline]
5 . Brown, A. G., Corbett, D. F., Eglington, A. J. & Howarth, T. T. (1977). Structures of olivanic acid derivatives MM4550 and MM13902; two new, fused ß-lactams isolated from Streptomyces olivaceus. Journal of the Chemical Society Chemical Communications, 5235.
6 . Aoki, H., Sakai, H., Kohsaka, M., Konomi, T. & Hosoda, J. (1976). Nocardicin A, a new monocyclic ß-lactam antibiotic. I. Discovery, isolation and characterization. Journal of Antibiotics 29, 492500.[ISI][Medline]
7 . Asai, M., Haibara, K., Muroi, M., Kintaka, K. & Kishi, T. (1981). Sulfazecin, a novel ß-lactam antibiotic of bacterial origin. Isolation and chemical characterization. Journal of Antibiotics 34, 6217.[ISI][Medline]
8 . English, A. R., Retsema, J. A., Girard, A. E., Lynch, J. E. & Barth, W. E. (1978). CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization. Antimicrobial Agents and Chemotherapy 14, 4149.[ISI][Medline]
9
.
Narisada, M., Yoshida, T., Onoue, H., Ohtani, M., Okada,
T., Tsuji, T. et al. (1979). Synthetic studies on ß-lactam antibiotics.
Part
10. Synthesis of 7ß-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7-methoxy-3-{
[(1-methyl-1H-tetrazol-5-yl)thio]-methyl}-1-oxa-1-dethia- 3-cephem-4-carboxylic acid disodium
salt
(6059-S) and its related 1-oxacephems. Journal of Medicinal Chemistry 22, 7579.[ISI][Medline]
10 . Guthikonda, R. N., Cama, L. D. & Christensen, B. G. (1974). Total synthesis of beta-lactam antibiotics. VIII. Stereospecific total synthesis of (6) 1-carbacephalothin. Journal of the American Chemical Society 96, 75845.[ISI][Medline]
11 . Kim, C. U., Misco, P. F. & McGregor, D. N. (1979). Synthesis and antibacterial activity of 2-oxocephalosporins. Journal of Medicinal Chemistry 22, 7435.[ISI][Medline]
12 . Doyle, T. W., Belleau, B., Luh, B. Y., Conway, T., Menard, M. & Douglas, J. L. (1977). Nuclear analogs of ß-lactam antibiotics. II. Synthesis of O-2-isocephems. Canadian Journal of Chemistry 55, 484507.[ISI]
13 . Abraham, E. P. (1977). ß-Lactam antibiotics and related substances. Japanese Journal of Antibiotics 30, Suppl., S126.
14
.
Cohen, N. C., Ernest, I., Fritz, H., Fuhrer, H., Rihs, F.,
Scartazzini, R. et al. (1987). Are the known 2-cephems
inactive as antibiotics because of an unfavourable steric orientation of the 4
-carboxylic
group?
Synthesis and biology of two
2-cephem-4-ß-carboxylic acids. Helvetica Chimica Acta 70, 196779.[ISI]
15 . Mastalerz, H., Menard, M., Vinet, V., Desiderio, J., Fung-Tomc, J., Kessler R. et al. (1988). An examination of O-2-isocephems as orally absorbable antibiotics. Journal of Medicinal Chemistry 31, 11906.[ISI][Medline]
16 . Matsumoto, M., Horimoto, H., Shizuta, T., Ishikawa, H. & Kikuchi, M. (1993). OPC-20000s, novel parenteral cephalosporinsstructure and activity relations. In Program and Abstracts of the Thirty-Third Interscience Conference on Antimicrobial Agents and Chemotherapy, 887. American Society for Microbiology, Washington, DC.
17 . Hakimelahi, G. H., Shiao, M.-J., Hwu, J. R. & Davari, H. (1992). Syntheses of novel isopenam and isocephem antibiotics. Preparation of a retinamido derivative of a highly strained ß-lactam as potent anticancer agent. Helvetica Chimica Acta 75, 18407.[ISI]
18 . Hwu, J. R., Tsay, S.-C. & Hakimelahi, S. (1998). Syntheses of new isodethiaazacephems as potent antibacterial agents. Journal of Medicinal Chemistry 41, 46815.[ISI][Medline]
19 . Bryskier, A. (1995). Penems: new oralß-lactam drugs. Expert Opinion on Investigational Drugs 4, 70524.
20 . Gottstein, W. J., Eachus, A. H., Misco, P. F., Cheney, L. C., Msiek, M. & Price, K. E. (1971). ß-Lactam antimicrobial agents which possess antifungal activity. Journal of Medicinal Chemistry 14, 7702.[ISI][Medline]
21 . Sanyal, A. K., Chowdhury, B. & Banerjee, A. B. (1992). Generation of high antimycotic activity during degradation of ß-lactam antibiotics. Letters in Applied Microbiology 14, 2213.[ISI]
22 . Abdulla, R. F. & Fuhr, K. H. (1975). Monocyclic antibiotic ß-lactams. Journal of Medicinal Chemistry 18, 6257.[ISI][Medline]
23 . Jen, T., Dienel, B., Frazee, J. & Weisbach, J. (1972). Novel cephalosporins. Modification of the C-4 carboxyl group. Journal of Medicinal Chemistry 15, 11724.[ISI][Medline]
24
.
Baldwin, J. E., Lynch, G. P. & Pitlik, J. (1991). -Lactam analogues of ß-lactam antibiotics. Journal of
Antibiotics44
, 124.[ISI][Medline]
25 . Brandt, A., Bassignani, L. & Re, L. (1976). Synthesis of a novel class of penicillins: DL-5, 6-dehydropenicillins. Tetrahedron Letters No. 44, 397982.
26 . Wolfe, S., Godfrey, J. C., Holdrege, C. T. & Perron, Y. G. (1963). Anhydropenicillins: a novel rearrangement of the thiazolidine ring. Journal of the American Chemical Society 85,643 4.[ISI]
27 . Ternansky, R. J. & Draheim, S. E. (1993). Structure-activity relationship within a series of pyrazolidinone antibacterial agents. 1. Effect of nuclear modification on in vitro activity. Journal of Medicinal Chemistry 36, 321923.[ISI][Medline]
28 . Ternansky, R. J., Draheim, S. E., Pike, A. J., Counter, F. T., Eudaly, J. A. & Kasher, J. S. (1993). Structure-activity relationship within a series of pyrazolidinone antibacterial agents. 2. Effect of side-chain modification on in vitro activity and pharmacokinetic parameters. Journal of Medicinal Chemistry 36, 32249.[ISI][Medline]
29 . Nozaki, Y., Katayama, N., Harada, S., Ono, H. & Okazaki, H. (1989). Lactivicin, a naturally occurring non ß-lactam antibiotic having ß-lactam-like action: biological activities and mode of action. Journal of Antibiotics 42, 8493.[ISI][Medline]
30 . Tamura, N., Matsushita, Y., Kawano, Y. & Yoshioka, K. (1990). Synthesis and antibacterial activity of lactivicin derivatives. Chemical and Pharmaceutical Bulletin 38, 11622.
31 . Imming, P. (1995). Synthesis of the first penicillin derivatives with medium-sized lactam ring and of related thiazolidines. Archiv der Pharmazie 328, 20715.[ISI]
32 . Heinze-Krauss, I., Angehrn, P., Charnas, R. L., Gubernator, E. M., Gutknecht, E. M., Hubschwerlen, C. (1998). Structure-based design of ß-lactamase inhibitors. 1. Synthesis and evaluation of bridged monobactams. Journal of Medicinal Chemistry 41, 396171.[ISI][Medline]
33 . Singh, R. & Cooper, R. D. G. (1994). Synthesis and biological evaluation of 6-azabicyclo[3.2.0]hept-2-ene derivatives as potential antibacterial agents and ß-lactamase inhibitors. Tetrahedron 50, 1204964.[ISI]
34 . Hubschwerlen, C., Angehrn, P., Gubernator, K., Page, M. G. P. et al. (1988). Structure-based design of ß-lactamase inhibitors. 2. Synthesis and evaluation of bridged sulfactams and oxamazins. Journal of Medicinal Chemistry 41, 39725.
35
.
Christenson, J. G., Pruess, D. L., Talbot, M. K. &
Keith, D.
D. (1988). Antibacterial properties of (2,3)-- and (2,3) ß-methylene
analogs of
penicillin G. Antimicrobial Agents and Chemotherapy 32, 100511.[ISI][Medline]
36 . Wei, C.-C., Christenson, J. G., Corraz, A. J. & Keith, D. D. (1991). (2,3)-a-methylenepenicillanic sulfone: synthesis and ß-lactamase inhibiting properties. Bioorganic and Medicinal Chemistry Letters 1, 436.
37 . Perboni, A., Rossi, T., Donati, D. & Gaviraghi, G. (1992). Tribactams: a novel class of ß-lactams. In Recent Advances in Antiinfective Chemistry (Bentley, P. & Ponsford, D., Eds), pp. 2133. Royal Society of Chemistry, London, UK.
38 . Di Modugno, E., Erbetti, I., Ferrari, L., Galassi, G., Hammond, S. M. & Xerri, L. (1994). In vitro activity of the tribactam GV104326 against Gram-positive, Gram-negative and anaerobic bacteria. Antimicrobial Agents and Chemotherapy 38, 23628.[Abstract]
39 . Spry, D. O. (1973). Synthesis of C-2-C3-tricyclic cephalosporins. Journal of the Chemical Society: Chemical Communications, 6712.
40 . Hanessian, S. & Reddy, G. B. (1994). Synthesis of tricyclic ß-lactams. Functionally and topologically novel carbacephems. Bioorganic and Medicinal Chemistry Letters 4,2285 90.
41 . Angehrn, P., Bohringer, M., Huberschwerlen, C., Page, M. G. P., Pflieger, P. et al. (1996). Bridged carbacephems as antibacterial agents: synthesis and structure-activity relationships. Abstracts of Thirty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract F158, p. 127. American Society for Microbiology, Washington, DC.
42 . Pflieger, P., Angehrn, P., Bohringer, M., Huberschwerlen, C., Page, M. G. P., Winkler, F. et al. (1996). Bridged carbacephems as ß-lactamse inhibitors: synthesis and structure-activity relationships. Abstracts of Thirty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract F159, p. 127. American Society for Microbiology, Washington, DC.
43 . Huberschwerlen, C., Angehrn, P., Boringer, M., Page, M. G. P., Specklin, J.-L., Kansy, M. et al. (1996). Bridged isooxa- and iso-cephems as ß-lactamase inhibitors and antibacterials: synthesis and structure-activity relationships. Abstracts of Thirty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract F157, p. 126. American Society for Microbiology, Washington, DC.
44
.
Hopkins, M. H. & Silverman, R. B. (1992).
ß-lactams: a new class of conformationally-rigid inhibitors of -aminobutyric acid
aminotransferase.Journal of Enzyme Inhibition
6,125
9.[ISI][Medline]
45 . Hori, S., Kanemitsu, K. & Shimada, J. (1993). Effect of cephalosporins on g-aminobutyric acid receptor binding with or without non-steroidal anti-inflammatory drugs. Journal of Antibiotics 46, 11458.[ISI][Medline]
46 . Doherty, J. B., Ashe, B. M., Argenbright, L. W., Barker, P. L. et al. (1986). Cephalosporin antibiotics can be modified to inhibit human leukocyte elastase. Nature 322, 1924.[ISI][Medline]
47 . Buynak, J. D., Rao, A. S., Ford, G. P., Carver, C., Adam, B., Geng, B. et al. (1997). 7-alkylidenecephalosporin esters as inhibitors of human leukocyte elastase. Journal of Medicinal Chemistry 40, 342333.[ISI][Medline]
48
.
Patick, A. K. & Potts, K. E. (1998).
Protease inhibitors as antiviral agents. Clinical Microbiology Reviews 11, 61427.
49 . Haley, T. M., Angier, S. J., Borthwick, A. D., Montgomery, D. S. et al. (1998). Investigation of the covalent modification of the catalytic triad of human cytomegalovirus protease by pseudo-reversible ß-lactam inhibitors and a peptide chloromethylketone. Journal of Mass Spectrometry 33, 124655.[ISI][Medline]
50 . Burke, J. R., Gregor, K. R., Padmanabha, R., Banville, J., Witmer, M. R., Davern, L. B. et al. (1998). A ß-lactam inhibitor of cytosolic phospholipase A2 which acts in a competitive reversible manner at the lipid/water interface. Journal of Enzyme Inhibition 13, 195204.[ISI][Medline]
51 . Sugatani, J., Saito, K. & Honjo, I. (1979). In vitro actions of some antibiotics on phospholipases. Journal of Antibiotics 32, 7349.[ISI][Medline]
52 . Kitchin, J., Bethell, R. C., Cammack, N., Dolan, S., Evans, D. N., Holman, S. et al. (1994). Synthesis and structure-activity relationships of a series of penicillin-derived HIV proteinase inhibitors: heterocyclic ring systems containing P1' and P2' substituents. Journal of Medicinal Chemistry 37, 370716.[ISI][Medline]
53 . Hamilton-Miller, J. M. T. (1994). Dual-action antibiotic hybrids. Journal of Antimicrobial Chemotherapy 33, 197200.[ISI][Medline]
54 . Vrudhula, V. M., Svensson, H. P. & Senter, P. D. (1995). Cephalosporin derivatives of doxorubicin as prodrugs for activation by monoclonal antibody>ß-lactamase conjugates. Journal of Medicinal Chemistry 38, 13805.[ISI][Medline]
Received 15 March 1999; accepted 8 October 1999