Chapter 12. Antibacterial Agents

Section 111 - Chemotherapeutic Agents Editor: Jacob J. Plattner Abbott Laboratories, Abbott Park, IL Chapter 12. Antibacterial Agents David R. White and Lorraine C. Davenport The Upjohn Company, Kalamazoo, MI 49001 Introduction - Major areas o f antibiotic research reported in 1989 include the quinolones, p-lactams, glycopeptides and a variety of other compounds which are active against methicillinresistant 5. aureus (MRSA). Macrolides are discussed in Chapter 13. Quinolones - The proceedings of the Second International Symposium on New Quinolones and the proceedings of the International Telesymposium on Quinolones were recently published (1, 2). A recent review highlights advances including improved Gram-positive, anaerobe, Chlamydia activity and i n some cases improved pharmacokinetics i n comparison w i t h ciprofloxacin (1)(3). Other reviews have been published covering t h e bacteriology, pharmacokinetics and clinical experience of the newer quinolones (4-6). Papers covering the clinical utility of quinolonesas a class have also been published (7-9). An updated review o n structure-activity relationships was published, pointing o u t that w i t h the exception of the C-4 position, every position o f the quinolone has n o w been successfully modified (10) A new thiazetoquinolone, NAD-394 (3,and its prodrug NAD-441A [N-(5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl NAD-3941 were disclosed. NAD-394 (3has broad spectrum activity i n vitro and its prodrug NAD-441A is 2-3x more potent than ofloxacin (1) vivo (1 1). The difluorinated benzothiazine, MF-961 (9, is roughly as active as ofloxacin (12). A series of benzo [i, j ] quinolizine 2-carboxylic acids was prepared in which the 8-methylamino and 8-ethylarnino analogs (I)showed significant activity 5.5. aureus and Acinetobacter strains compared t o ciprofloxacin, but otherwise were generally less active (13). A study has shown that the N-l-(4'-difluoromethoxyphenyl) residue was halogen-like when compared t o 4'-Br or 4'-CI, but did not compare w i t h 4'-F for overall activity (14). Studies were conducted to optimize the activity of the previously reported l-t-butylsubstituted quinolones and naphthyridines (15) by altering the C-7 piperazine residue. The 2methylpiperazine derivative (6J has t h e best activity; the Z(5)-methylpiperazine i n t h e a 7naphthyridine series i s more active than the (R)-isomer (16). Danofloxacin (CP-76,136) diazabicycloquinolone, is being evaluated for diseases i n food-producing animals because of its good pharmacokinetics, activity, and solubility (17-20).

(z),

The effect of absolute and relative stereochemistry of C-7 pyrrolidinyl substituents was studied (21). The most active compound i n this series is the 3R, 1'5 isomer DS-4524 (8J WIN57273 (%, a 7-pyridinyl quinolone, is more active than ciprofloxacin G . Gram-positive but less active fi. Gram-negative bacteria. WIN-57273 showed excellent activity against certain methicillin, gentamicin and even some ciprofloxacin resistant organisms It is also more active than ciprofloxacin AIDS related Legioneflasp and Mycobacteriurn avturn (22-29) A series of enantiomeric tetracyclic quinolones i n which the basic C-7 substituent i s linked t o C-8 by means of an oxygen atom are all comparable or slightly better than ofloxacin. The enantiorner ( l O Jappears to be the best compound in vivo (30).

ANNUAL REPORTS I N MEDICINAL CHEMISTRY--25

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Copyright 0 1989 by Academic Press, h c . All rights of reproduction in any form reserved.

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In a study of norfloxacin prodrugs, i t was found that N-masked congeners having acidic hydrogens on the carbon a t o the nitrogen atom liberate norfloxacin in vivo (31). In another study, i t was found that the rearrangement product (11)obtained by the chemical oxidation of N-[(5-methyl-2-oxo-l,3-dioxol-4-yl)methyI] norfloxacin also acts as a prodrug o f norfloxacin

(32). A recent study determined that the 6-fluoro-7-(4-hydroxypiperazin-l-yl) quinolone derivatives were superior t o their corresponding deoxy analogs, norfloxacin, ciprofloxacin and enoxacin. Subsequently 11 was found t o be >5x more potent than ciprofloxacin i n vivo vs. 5. aureusand E. coli(33).

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0

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The mechanism of resistance t o quinolones is still undergoing active investigation. A recent review suggests resistance i s due t o mutations affecting DNA gyrase and/or drug permeability (34). A combination of decreased permeability and DNA susceptibility was seen i n experimental endocarditis with Pseudomonas aeruginosa (35) and i n experimental peritonitis w i t h Enterobacter cloacae ( 3 6 ) . Decreased permeability was seen as the mechanism o f resistance in E. coli mutants (37,38) ,while changes i n DNA gyrase were cited i n studies on E. coli (39, 40) and Serratia marcescens (41).Widespread resistance among MRSA was found i n a TelAviv hospital (42). A proposed cooperative quinolone-DNA binding model for the inhibition o f DNA gyrase has been published (43), along with supporting experimental evidence. In this model

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the quinolone molecules bind t o a gyrase-induced DNA site during the "gate-opening" step o f the supercoiling process @ hydrogen bonds t o the unpaired bases. The formation o f tyrosinequinolone binary complexes was also determined i n a U V photometric study (44). The use of calf thymus topoisomerase II inhibition assays as a predictor of cytotoxicity is being investigated by several groups w i t h varying results (45-47). There is a large difference among the quinolones in their selectivities between the bacterial enzyme and its eucaryotic counterpart. A recent paper points o u t t h a t quinolones administered intravenously to mice concomitantly with oral biphenyl acetic acid, a metabolite o f fenbufen, provoked clonic convulsions and subsequent death at doses of 6.25 mg/kg or more when the compound has a non-substituted piperazine moiety at the 7 position. There was a close correlation between the epileptogenic activities of quinolones and their inhibitory potencies for [3H] muscimol binding t o GABA receptor sites (48). Another study linked CNS side-effects of quinolones t o their induction o f increased interleuken-2 levels in phytohemagglutinin (PHA)-stimulated human lyphocytes (49) at clinically achievable concentrations (5 pg/ml). Following previous reports of in vitro activity 5. Plasmodium falciparum, norfloxacin was found t o be effective i n humans w i t h falciparum malaria (50). Ciprofloxacin, difloxacin and ofloxacin were found t o have good activity (MIC50 1 pg/ml) 5. Mycoplasma horninis (51). Quinolones were also found effective i n experimental Leishmania donovani (52). Additional information was presented on KB-5246 Tissue levels were 4-4Ox plasma levels while CSF levels were -10-20% of plasma levels (53). AT-4140 was the most active quinolone tested in vitro vs. C. trachornatis (54) and Legionella sp. (55). In experimental bacterial prostatitis ( E . coli-or E. faecalis) AT-4140 was the most effective quinolone tested (56). More detailed in vitro and in vivo information on BMY-40062 has appeared, showing that this agent compares favorably w i t h ciprofloxacin (57, 58). a-Lactarns - Research has focused on structures having stability to lactarnase enzymes and improved pharmacological properties BRL 44154 is the preferred compound i n a series of alkoxyimino penicillins synthesized (59) due t o its activity MRSA, stability t o staphylococcal @-lactarnase (60) and ease of synthesis. BRL 44154 is effective i n a series of experimental infections i n the mouse produced by both Gram-positive and Gram-negative organisms including p-lactamase producing staphylococci (61). A new penem with high oral availability, FCE 25199 was disclosed. It is generally comparable t o imipenem in vitro (62, 63). A novel @-methylcarbapenem LJC 10627 was shown t o be about two times as active as imipenem s. Gram-negative bacteria in vitro and i n vivo. LJC 10627 is stable t o renal dihydropeptidase and a pharmacokinetic study indicated 95% urinary recovery in monkeys (64-56). Additional information on the synthesis and @-lactamaseactivity of BRL-42715 has been published (67). BRL-42715 inhibits a broad range of plasmid-mediated 0-lactamases, including the class V OXA group of enzymes and ail of the class I cephalosporinase enzymes (68) A synthesis of ylactam analogs of oxa-penams (I7J was undertaken and the compounds were found t o be inactive (69)

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A n e w 1-carba- 1 -dethia-cephalosporin, LY-249902 (Is), s h o w e d enhanced bioavailability over cefetarnet i n the monkey, but not i n the dog (70) CP 6162 (l9), a new parenteral cephalosporin, was reported t o have potent in vitro and in vivo activity against @lactarnase producing Gram-negative bacteria including Ps aeiuginosa (71) A n e w broad spectrum cephalosporin, GR-69153 with an extended half-life (t 1/2 = 3 1/2 hr, man) was also presented A 1 g dose gives plasma levels exceeding the M I C g 0 for 24 hr for many organisms (72, 73). A series of C(3)-cyclopropyl cephalosporins and carbacephalosporins was synthesized. The phenylglycyl analogs (2lJ showed better Gram-positive activity than cefaclor while the m-methylsulfonamidophenylglycyl cephalorporin (22J had a markedly longer half-life than (2l-) (74, 75) KP-736 (23J is a new parenteral cephalosporin w i t h high activity E. Pseudomonas sp. inciuding multiple drug-resistant strains. In vivo, KP-736 is comparable t o ceftazidimes. Gram-positive infectionswhile i t is -6xaseffectives. fseudomonas(76-80). SCE-

(a),

Plattner Ed.

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112 -

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2787 (24J is a new P-lactamase-stable parenteral cephalosporin which is active E.5. aureus and Ps. aeruginosa both in vitro and in vivo. It has been selected as a candidate for clinical evaluation (81-86). KP-736. as well as CP-6162 and GR-69153. are noteworthy examples o f structures which exploit the ton 8-dependent iron transport pathway. An extensive review o f the chemistry of therapeutically important, siderophore containing molecules has appeared (87). A structure activity study t o improve the i n vivo efficacy and pharrnacokinetics o f SQ 83,325 resulted i n the synthesis of SQ 83,989 The protonated aminomethyl substituent on the 5-hydroxy-4-pyridone ring is the optimal substituent for improving both in vivo efficacy and urinary excretion (88).

(m.

A n acyclic phosphonate monoester, m-carboxyphenyl phenylacetamidomethylphosphonate, has been found to give rapid inhibition of a class C 0-lactamase (89).

0 Glycopeptides - A proposal has been made t o name t h e vancomycin-glycopeptides "dalbaheptides" from DAL (D-alanyl-D-alanine) B (binding) A (antibiotics) w i t h a HEptapeptidic structure (90). A further distinction would distinguish the glycodalbaheptides which have only sugars a t t a c h e d t o t h e p e p t i d e core (vancomycins, ristocetins, a v o p a r c i n s ) a n d lipoglycodalbaheptides which have a fatty acid chain attached t o the core (teicoplanins, kibdelins, parvodicins)

A recent approach t o vancomycin derivatives involved the biotransformation o f vancomycin by Actinornadura citrea, leading t o its biologically inactive hexapeptide core. This was the first bioconversion of a glycopeptide antibiotic by a non-glycopeptide-producing culture (91). Another approach t o vancomycin derivatives involved oxidative phenolic coupling w i t h thallium nitrate t o yield tetrapeptide (26) which i s expected t o bind t o N-acyl-D-Ala-Dalanine (92) Arene-manganese tricarbonyl complexes were used i n t h e synthesis o f arylglycines as potential sub-units in the synthesis o f ristocetin and vancomycin (93). OH

Studies have probed the influence of thioureas and isothiouronium salts on teicoplanin aglycone (94), and the intramolecular cyclization o f the isothioronium derivative was investigated (95). Sequential removal of chlorine from teicoplanin gave decreased binding affinity and decreasing antibacterial activity (96). Base catalyzed elimination of N-acetyl-P-Dglucosamine from teicoplanin gave unsaturated products. The 35,52-unstaturated compound maintained binding affinity and antibacterial activity while the 34.35-unsaturated compound

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did not, due t o changes i n molecular configuration (97). N63-carboxamide and N63carboxypeptides o f teicoplanin showed some improved activity which was dependent on ionic and lipophilic character and on the type and number of sugars present (98, 99). Deamination o f teicoplanin resulted in loss of activity (100). New minor components of the teicoplanin complex have been isolated from large scale fermentations o f Actinoplanes teichornyceticus (101) and designated as related substances RS-1 through RS-4. Biological activity was not disclosed. A-42867 (27J i s a new glycopeptide isolated from a Nocardia nov. sp. ATCC 53492 which has biological activity comparable t o the other members of the group (102). UK-68,597 (28J is another new member of this class which was isolated from Actinoplanes sp. ATCC 53533 (103, 104). Several papers were published exploring the structural relationships between the recently reported orienticins, chloroorienticins and A82846 complex (1 05-107). R-R‘

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(m

Miscellaneous - The antituberculosis activity o f DUP-721 was compared t o a nitroimidazole CGI-17341 3(OJ In vitro both were active 9. Mycobacteria tuberculosis (DUP 1.25-4pg/mL, CGI 0.06-0.3 pg/mL) while both were inactive vs. M. awiurn intracellulare (108). A short, chiral synthesis of the oxazolidinone DUP-721 i n 60% yield has been published (109) and many other analogs were synthesized using this synthetic sequence i n a structure-activity report (1 10). Coumermycin analogs have come under renewed interest due t o their activity 9. MRSA and their mechanism of action as an inhibitor of DNA gyrase. The most promising analog of the series was (11)although i t was less active than coumermycin A1 (1 11). Cvclic Peptides - The structure o f the ramoplanin complex (A-16686) was published (1 12,113). This complex i s active 9. aerobic and anaerobic Gram-positive bacteria including MRSA. Hypeptin is a cyclic peptide isolated from a Pseudomonassp. with activity mainly 5.aerobic and anaerobic Gram-positive bacteria (1 14). The janthinomycins (32J are a complex of macrocyclic peptide lactones produced by lanthinobacteriurn liwrdurn which were 2-4 times more active than vancomycin in vitro (including MRSA) and were roughly equivalent i n vivo vs. 5. aureus (ED50 c 1 . 6 for 1, 2.0 for vanco.). Janthinomycin A and B are unique i n that P-hydroxytryptophan and P-ketotryptophan have not previously been isolated as natural products. (1 15, 116). UK-63052 complex is a group o f quinomycin-like peptides isolated from Streptornyces braegensisss japonicus having activitys. 5. aureus (MIC <0.20-1.56 pg/mL) (1 17). Mersacidin i s a sulfur-containing peptide produced by a Bacillus sp which was -2x more active in vivo than vancomycin 5.5. aureus including MRSA (118). Thioxamycin is a thiopeptide isolated from a Streptornyces sp. and is mainly active 9. anaerobes. It is also active 9. 5. aureus (MIC 3.13 pglml) (1 19). A-102558 is quite similar i n structure and spectrum t o thioxamycin and may be targeted as a g r o w t h promotant i n animals. The A-10255 complex was produced by Streptornyces gardneri (120-123) Other Anti-staphylococci Antibiotics - The structure o f the previously reported ficellomycin was elucidated (124). The altromycins are a group of pluramycin-like antibiotics isolated from a nocardioform actinomycete using a super-sensitive Pseudomonas aeruginosa strain (125,126). A-82810 is a new polyether antibiotic produced by Actinornadura fibrosa which i s also an anthelmintic and insecticidal compound (127). CP-73064 is another new polyether isolated from Streptornyces sp ATCC 53523 (128).

as OH

0

I co

OH

u

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116

L-lle

Plattner Ed

- D-erythro-BHL - L-Thr - L-Ser - D-erythro-BHL - AAbu - D-Ser - X - D-Orn - L-Phe Janthlnomycln A, X = ihreff-B-hydroxytryptophan Janthlnornycln B, X = B-ketotryptophan Janthinornycln C, X = dehydrotryptophan AAbu 2,3-dehydro-a-arnlnobutyrlc acld RHL=B-hydroxyleuclne

32

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Rev. Infect. Dis., lJSuppl.5,5897 (1989). Quinolones Proceedinqs of an International Telesymposium," P.B.Fernandes, Ed., J.R. . . ProusScience Publishers, Barcelona, Spain, 1989. R. Janknegt and Y.A. Hekster, Pharm. Weekbl. Sci. Ed., lJ,33 (1989). E.A. Bulger and D.M. Parenti, Drug Ther., l9, 131 (1989) F. Cabrera, T. Vial, I. Grosset Grange and J. Descotes, Lyon Pharm., 40& 269 (1989). D.C. Leysen. A. Haemers and S.R. Pattyn, Antimicrob. Agents Chernother., 33, 1 (1989). H.C. Neu, Pharrnac. Ther., 41,207 (1989). J.S. Wolfson and D C. Hooper, Antirnicrob. Agents Chemother., 33, 1655 (1989). D.C. Hooper and J.S. Wolfson, Antirnicrob. Agents Chernother., 3,1662 (1989). D T.W. Chu and P.B. Fernandes, Antirnicrob. Agents Chernother., 33, 131 (1989). T. Nishino, M . Otsuki, M. Ozaki, M. Matsuda and K. Kimura, 29th ICAAC, 1253 (1989). P.G. Pagella, P. Terni, P.L. Rugarli, A. Papagina, 5 . Maiorana and R. Mattina, 29th ICAAC, 1251 (1989). F. Sauter, U. Jordis, P. Martinek and G. Cai, Sci. Pharrn., 5J,7 (1989). W. Xiao, R. Krishnan, Y.4. Lin, E.F. DelosSantos, N.A. Kuck, R.E. Babine and 5 . 5 . Lang, Jr., J. Pharrn. Sci., 78,585 (1989). D. Bouzard, P. Di Cesare, M. Essiz, J.P. Jacquet, R. Rernuzon, A. Weber, T. Oki, and M . Masuvoshi. 1. Med. Chern.. 32. 537 (1989). D. Bobzard, P. Remuzon, P x i Cesare, M'. Essiz, J.P. Jacquet, J.R. Kiechel, R.E. Kessler and J. Fung-Tom, 29th ICAAC, 1247 (1989). P.R. McGuirk, M.R. Jefson, D.D. Mann. M.S. Hindahl, C.P. Cornell and F.H. Weber, 29th ICAAC, 1 186 (1989) P R. McGuirk. M.R. Jefson. T.R. Shrvock and T K. Schaaf. 29th ICAAC. 1187 (1989) G M Frame, D D Mann and M J Lynch, 29th ICAAC, 11'88 (1989) D D Mann, 29th ICAAC, 1189 (1989) Y Kirnura. K Sato, 5 Atarashi, I Havakawa, M Sato, and Y Osada, 29th ICAAC. 1192 ( 1989). M. Reuman S.J. Daurn, B. Singh, S A. Coughlin, D M . Sedlock, J B Rake and G.Y Lesher, 29th ICAAC, 1 193 (1989). D.M. Deuel, D.M. Sedlock, G.Y. Lesher, S.J Daurn, M.P. Wentland, M . Reurnan, M . A . McKinlayand J.B. Rake, 29th ICAAC, 1194 (1989). C.B. Inderlied, F.G. Sandoval, J Peters and L S Young, 29th ICAAC, 1195 (1989). G.M. Eliopoulos, K. Klirnrn, L.B. Rice, M J. Ferraro and R.C Moellering, 29th ICAAC, 1196 I1 9891 G W Kaatr and 5 M Seo, 29th ICAAC, 1197 (1989) D M Yocum, E M Robbiano, R A Venezia and R M Echols, 29th ICAAC, 1198 (1989) R A Dobson. D M Sedlock and J B Rake. 29th ICAAC. 1199 (1989) P.H. Edelstein and M.A.C. Edelstein, Antirnicrob. Agents Chernother, 33, 2132 (1989) I . Kompis, P. Angehrn and W. Muller, 29th ICAAC, 1250 (1989). H. Kondo, F. Sakamoto, Y. lnoue and G. Tsukarnoto, J. Med. Chern., 32, 679 (1989). H. Kondo, F. Sakarnoto, T. Uno, Y. Kawahata, and G. Tsukarnoto, 1. Med. Chern., 32, 671 (1989). T. Uno, T. Okuno, M . Taguchi, K. luchi, Y. Kawahata, M. Sotornura and G. Tsukarnoto, J. Heterocyclic Chern. 26 393 (1989). L.J.V. Piddock and k G i s e , J. Antirnicrob. Chernother., 23, 475 (1989). S. Charnberland, A.S. Bayer, T. Schollaardt, S.A. Wong and L.E. Bryan, Antimicrob. Agents Chernother., 33,624 (1989). C. Lucain, P. Regarney, F. Bellido and J-C. Pechere, Antimicrob. Agents Chernother., 33, 937 119891. D.C.Hooper, J.S. Wolfson, K.S. Souza, E.Y. Ng, G.L. McHugh and M.N. Swartz, Antirnicrob. Agents Chernother., 3 , 2 8 3 (1989). S.P. Cohen, L.M. McMurry, D.C. Hooper, J.S. Wolfson and S.B. Levy, Antirnicrob. Agents Chernother., 33, 1318(1989).

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M.E. Cullen, A.W. Wyke, R. Kuroda and L.M. Fisher, Antirnicrob. Agents Chernother., 33, 886 (1 989). S . Nakarnura, M . Nakarnura, T. Kojirna and H. Yoshida, Antimicrob. Agents Chernother., 33,254 (1989). K. Fujirnaki, T. Fujii, H. Aoyarna, K.-I. Sato, Y. Inoue, M. lnoue and S. Mitsuhashi, Antirnicrob. Agents Chernother., 33, 785 (1989). I. Shalit, S.A. Berger, A. Gorea anbH. Frirnerman, Antirnicrob. Agents Chernother., 33, 593 (1989). L.L. Shen, L.A. Mitscher, P.N. Sharrna, T.J. O’Donnell, D.W.T. Chu, C.S. Cooper,T. Rosen and A.G. Pernet, Biochemistry, 28,3886 (1989). H. Robaux, V. Loppinet and J.L. Monal, Pharrn. Weekbl. Sci. Ed., lJSuppl. C, C6 (1989). N. Moreau, H. Robaux, X. Tabary, J.R. Kiechel and D. Bouzard, 29th ICAAC, 1248 (1989). K. Hoshino, K. Sato, T. Une and Y. Osada, Antirnicrob. Agents Chernother., 33, 1816 (1989). J.F. Barrett, T.D. Gootz, P.R. McGuirk, C A. Farrell and S.A. Sokolowski, Antirnicrob. Agents Chernother., 33,1697 (1989). K. Akahane, M. Sekiguchi, T. Une and Y. Osada, Antirnicrob. Agents Chernother., 33, 1704 (1989). K. Riesbeck, J. Anderson, M. Gullberg and A. Forsgren, Proc. Natl. Acad. Sci. USA, 86, 2809 ( 1989) P 5. Sarma, Ann. Intern. Med., =,336(1989). G.E. Kenny, T.M. Hooton, M.C. Roberts, F D Cartwright and 1. Hop, Antirnicrob. Agents Chernother. 33, 103 (1989). W. Raether, H. Seidenath and J. Hofrnann, Parasitol Res., 75,412 (1989). T. Kawashirna, T. Harnada, Y. Inoue, N. Awata, F. Sakarnoto and N. Akaike, 29th ICAAC, 1243 (1989). K. Nakata, H. Maeda, A. Fujii, 5. Arakawa, K. Umezu and 5. Karnidono, 29th ICAAC, 1200 ( 1989). T. Kojirna, M . lnoue and 5.Mitsuhashi, Antirnicrob Agents Chernother., 33, 1980 (1989). 5.Arakawa, K. Nakata, K. Urnezu and S. Karnidono, 29th ICAAC, 1201 (1989). N.X. Chin, G. Saha and H.C. Neu, 29th ICAAC, 1249 (1989). J. Fung-Tornc, J.V. Desiderio, Y.H. Tsai, G. Warr and R.E. Kessler, Antirnicrob. Agents Chernother., 33,906 (1989). P.C.A. Chapman, A.J Eglington, R.L. Elliott, B.C. Gasson, J.D. Hinks, J. Lowther, D.J. Merrikin, M.J. Pearson and R.J. Ponsford, 29th ICAAC, 89 (1989). E.J. Catherall, N.R Eaton, G.K. Hill, D.J.Merrikin and L. Mizen, 29th ICAAC, 90 (1989). P.C.A. Chapman, D.J. Merrikin, R.J. Ponsford and H. Srnulders, 29th ICAAC, 91 (1989). G. Meinardi, R. Rossi, P. Castellani and C.D. Bruna, 29th ICAAC, 85 (1989). C D. Bruna, P. Castellani, D. Jabes, G. Meinardi, R. Rossi, G. Franceschi, E. Perrone and R. Roncucci, 29th ICAAC, 87. M. Hikida, M. Yoshida, K. Nishiki, Y. Furukawa, K. Ubukata, M. Konno and 5. Mitsuhashi, 29th ICAAC, 221 (1989). P.J. Petersen, W.J. Weiss, N.V. Jacobus and R.T. Testa, 29th ICAAC, 222 (1989). N. Yarnashita, T Hirai, T. Watanabe, T. Kuroda, K. Kawashirna, M. Hikida, Y. Furukawa and T. Honda, 29th ICAAC, 223 (1989). N.F. Osborne, N.J.P. Broom, 5 . Coulton, J.B. Harbridge, M A. Harris and F.I. Stirling, J.C.5 Chern. Cornrnun., 371 (1989). K. Coleman, D.R J. Griffin, J.W J. Page and P.A. Upshon, Antirnicrob. Agents Chernother , 33, 1 580 (1989). Baldwin, R.T. Freeman and C.Schofield, Tetrahedron Lett., 30,4019 (1989) F.T. Counter, J.A Eudaly, W 1 Hornback, M.E. Johnson, R.J. Johnson, C.L Jordan, J.S. Kasher, J.E. Munroe, J.F. Quay, T.G. Spaur, W.E Wright, C.Y.E. Wu and L.L. Zornes, 29th ICAAC, 238 (1989). 5 Shibahara, K. lwamatsu, K. Atsumi and S Inoue, 29th ICAAC, 356 ( 1 989). J.A. Mackay, S.M. Harding, J.L Palmer and G.L. Evans, 29th ICAAC, 351 (1989). A.M. Harris, P. Acred, C.E. Newall, B E Looker and J.B. Ward, 29th ICAAC, 352 (1989). D.O. Spry, N.J. Snyder and J.5. Kasher, 29th ICAAC, 240 (1989). D.O. Spry, N.J. Snyderand J.S. Kasher, J. Antibiot., 42, 1653 (1989). Y Zarna, T. Naito, M . Hirose, M Yokoyarna, T. Saita, N. Ishiyarna, S Sanai and K. Saga, 29th ICAAC, 48 1 (1989). T. Maejirna and 5. Mitsuhashi, 29th ICAAC, 482 (1983). H. Senda, K, Sekine, W. Iwatani, 5 . Sanai, T. Arika and T. Yokota, 29th ICAAC, 483 (1989). H. Senda, K. Sekine, W. Iwatani, T. Arika, T. Maejirna and S Mitsuhashi, 29th ICAAC, 484 (1989). T. Awaji, K. Uda, T. Kawahara, H. Kisida, A. Terashima, T. Tanigaki and K. Minowa, 29th ICAAC, 485 (1989). A. Miyake, Y. Yoshirnura, M. Yarnaoka, T. Nishirnura, N. Hashirnoto and A. Irnada, 29th ICAAC. 486 11989). T Nakane, M lnoue and 5 Mitsuhashi, 29th ICAAC, 487 (1989) S Goto, S Mtyazaki, Y Kaneko, A TSUJIand S Kuwahara, 29th ICAAC, 488 (1989)

z.

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Section 111-ChemotherapeuticAgents

84.

Plattner Ed

T. Iwahi, M. Nakao, K. Okonogi, Y. Noji, T. Yamazaki and A. Irnada, 29th ICAAC, 489 (1989). 85. T. Nishino, M. Otsuki, Y. Noji and N. Tsuchimori, 29th ICAAC, 490 (1989). 86. T. Yamazaki, Y. Kita. Y. Izawa, T. liwahi, M. Nakao and A. Irnada, 29th ICAAC, 491 (1989). 87. M.J. Miller, Chem. Rev., 89,1563 (1989). 88. U.D. Treuner, P. Ermann, S. Jendrzejewski and H. Straub, 29th ICAAC, 236 (1989). 89. R.F. Pratt, Science, 246,917 (1989). 90. F. Parenti and B. Cavalleri. J. Antibiot., 42, 1882 (1989). 91. M.J. Zmijewski, R.M. Logan, G. Marconi, M. Debono, R.M. Molloy, F. Chadwell and B. Briggs, J. Natural Prod., 52,203 (1989). 92. Y. Suzuki, S. Nishiyarna and S. Yamamura, Tetrahedron Lett., 30, 6043 (1989). 93. A.J. Pearson, P.R. Bruhn, F. Gouzoulesand S.-H. Lee, J.C.S. Chem. Commun., 659(1989). 94. A. Trani, P. Ferrari, R. Pallanza and R. Ciabatti, 1. Antibiot., 42, 1268 (1989). 95. A. Trani, P. Ferrari, R. Pallanza and R. Ciabatti, J. Antibiot., 42, 1276 (1989). 96. A. Malabarba, F. Spreafico, P. Ferrari, J. Kettenring, P. Strazzolini, G. Tarzia, R. Pallanza, M. Berti and B. Cavalleri, J.Antibiot., 42, 1684 (1989). 97. A. Malabarba, A. Tani, G. Tarzia, P. Ferrari, R. Pallanza and M . Berti, J. Med. Chern., 32, 783 11989). ---, 98. A. Malabarba, A. Trani, P. Strazzolini, G. Cietto. P. Ferrari, G. Tarzia, R. Pallanza and M. Berti, J. Med. Chem. 32,2450 (1989). 99. A. Malabarba, P. Ferrari. G. Cietto, R. Pallanza and M. Berti, J. Antibiot., 42, 1800 (1989). 100. A. Trani, P. Ferrari, R. Pallanza and G. Tarzia, J. Med. Chern., 32, 310 (198q. 101. A. Borghi, P. Antonini, M. Zanol, P. Ferrari, L.F. Zerilli and G.C. Lancini, J. Antibiot., 42, 361 (1989). 102. E. Riva, L. Gastaldo, M.G. Beretta, P. Ferrari, L.F. Zerilli, G. Cassani, E. Selva, B.P. Goldstein, M.Berti, F. Parenti and M. Denaro, J. Antibiot., 42,497 (1989). 103. J. Horsman, K.C. How, R.A. Monday, M.S. Pacey, J.C Ruddock, D.A. Wakefield, 1. Tone, H. Maeda, L.H. Huang and 1. Clancy, 29th ICAAC, 415 (1989). 104. J.C. Ruddock, N.J. Skelton and D.H. Williams, 29th ICAAC, 416 (1989). 105. R. Nagarajan, D.M. Berry and A.A. Schabel, J. Antibiot., 42, 1438 (1989). 106. R. Nagarajan, D.M. Berry, A.H. Hunt, J.L. Occolowitz an7A.A. Schabel, J. Org. Chem., 54, 983 (1989). 107. G.F. Gause, M.G Brazhnikova, N.N. Lornakina, T.F. Berdnikova, G.B. Fedorova, N.L. Tokareva, V.N. Borisova and G.Y. Batta, J. Antibiot., 42, 1790 (1989). 108. D.R. Ashtekar, R. Costa-Pereira, R. Ayyer, T. Shirinivasan, N. Vishvanathan and K. Nagarajan, 29th ICAAC, 889 (1989). 109. C.-L.J. Wang, W.A. Gregory and M.A. Wuonola, Tetrahedron, 45, 1323 (1989). 110. W.A. Gregory, D.R. Brittelli, C.-L.J. Wang, M.A. Wuonola, R.J. McRipley. D.C. Eustice, V.S. Eberly, P.T. Bartho1omew.A.M. Slee and M. Forbes, J. Med. Chern., 32, 1673 (1989). 1 1 1. Y. Ueda, J.M. Chuang, L.8 Crast, Jr. and R.A. Partyka, J. Antibiot ,Q, 1379 (1989). 112. R. Ciabatti, J.K. Kettenring, G. Winters, G. Tuan, L. Zerilli and B. Cavalleri, J. Antibiot., 42, 254 (1989). 113. J.K. Kettenring, R. Ciabatti, G. Winters, G Tamborini and B. Cavalleri. J. Antibiot., 42, 268 (1989). 114. J. Shoji, H. Hinoo, T. Hattori, K. Hirooka, Y. Kirnura and T. Yoshida, J. Antibiot., 42, 1460. 115. J. O'Sullivan, J. McCullough, J.H. Johnson, D.P. Bonner, J.M. Clark, L. Dean and W.H. Trejo, 29th ICAAC, 407 (1989). 116. J.H. Johnson, A.A. Tymiak and M.S. Bolgar, 29th ICAAC, 408 (1989). 117. M.J. Rance. J.C. Ruddock, M.S. Pacey, W.P. Cullen, L.H. Huang, M.T. Jefferson, E.B. Whipple, H. Maedaand J. Tone, 1. Antibiot., 42,206 (1989). 118. B.N. Ganguli, 5. Chatterjee, 5. Chatterjee, R. Jani, G.P. Pai, D.K. Chatterjee, J Blumbach, H. Kogler, H.W. Fehlhaber, V. Teetz, N. Klesel and G. Seibert, 29th ICAAC, 413 (1989). 119. M. Matsumoto, Y. Kawarnura, Y. Yasuda, T. Tanirnoto, K. Matsumoto, T. Yoshida and J. Shoji, J. Antibiot., 42, 1465 (1989). 120. K.H. Michet, M.M. Hoehn, L D. Boeck, J.W. Martin, M.A. Abbott, 0 W. Godfrey and F P. Mertz, 29th ICAAC, 409 (1989). 121. M. Debono, R.W. Molloy, J L Occolowitz, J.W. Paschal, K.H. Michel and J.W. Martin, 29th ICAAC, 41 0 (1989). 122. F.T. Counter, P.W Ensmin er and C.Y E Wu, 29th ICAAC, 41 1 (1989). 123 L.F. Richardson, C.C. Schei?inger and D.A. Becker, 29th ICAAC, 412 (1989). 124. M . 4 . Kuo. D.A. Yurekand S.A. Mizsak. J. Antibiot.. 42.357 (1989). 125 M Jackson, J P Karwowski, R J Theriault, D J Hardy, S J Swanson, G J Barlow and P M Tillis, 29th ICAAC, 421 (1989) 126 G M Brill, J B McAlpine, D N Whittern and A M Buko, 29th ICAAC, 422 (1989) 127 R L Hamill, L D Boeck, W L Current, R P Massina. F B Mertz. J L Occolowitz. J W Paschal and R.C. Yao. 29th ICCAC. 423 (1989j. 128. J.R. Oscarson, W.P. Cullen, Y. Kojima, H. Maeda. S. Nishiyarna, A.P. Ricketts, J. Tone and K. Tsukuda, 29th ICAAC, 424 (1989).

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