Derivatives of a novel cyclopeptolide. 1. Synthesis, antifungal activity, and structure-activity relationships.

The synthesis of a series of derivatives of the novel antifungal cyclopeptolide 1, which consists of nine S-amino acids and R-lactic acid, is described. Besides functional group variation of MeAsp4 (esters 2a-d, amides 3a-d, alcohol 4, and its derivatives) and Tyr(Me)9 (demethyl derivative 8, ethers 12a-f, 13, and oxidative degradation of the phenyl group to 14), opening of the lactone by LiOH in THF/H2O allowed manipulation of the hydroxy group of R-Hypr10 in the resulting acyclic peptide 15. Recyclization of 15 under Mitsunobu conditions followed by deprotection led to the S-Hypr10 analogue 17 of 1. Cyclic decapeptides 33 and 34 as well as cyclic undecapeptides 35 and 36 were obtained via the corresponding modified linear peptides 23, 24, 27, and 28 by cyclization. Methylation of all secondary amide groups by CH3I and KH/18crown6 gave the permethylated compound 37. Two of the derivatives (17 and 34) showed superior activities against yeasts in vitro at pH 6.5 as compared to 1, but not at a lower pH (4.5).

Derivatives of a novel cyclopeptolide. 2. Synthesis, activity against multidrug resistance in CHO and KB cells in vitro, and structure-activity relationships.

A series of derivatives of the novel cyclopeptolide 1 was prepared, and their ability to chemosensitize multi drug resistant CHO and KB cells in vitro was evaluated. In contrast to the parent compound, several of the derivatives were found to be highly active. In particular, conversion of the R-lactic acid residue of 1 into its S-isomer via lactone ring cleavage and recyclization with inversion resulted in a marked enhancement of activity. Some of these derivatives (e.g., 15a, SDZ 280.446) belong to the most potent resistance modulating compounds known so far.

Synthesis and structure-activity relationships of phenyl-substituted benzylamine antimycotics: a novel benzylbenzylamine antifungal agent for systemic treatment.

Derivatives of the benzylamine antimycotics with an extra phenyl ring incorporated in the side chain have been prepared and their antifungal activity evaluated. The potency is strongly dependent on the distance between the two phenyl groups and the type of spacer. Linking the aryl rings with a quaternary carbon atom resulted in the identification of highly active compounds 7f and 12a, having a novel 4-benzylbenzylamine side chain. Compound 7f and its 7-benzo[b]thienyl analogue 12a show significantly enhanced efficacy, in particular against Candida albicans, and are among the most potent allyl/benzylamine antimycotics identified so far. Extended investigations with the benzylbenzylamine derivative 7f revealed that, in addition to the enhanced antimycotic profile, the compound is the first representative of the benzylamine antimycotics suitable for systemic treatment.

Reversion of the P-glycoprotein-mediated multidrug resistance of cancer cells by FK-506 derivatives.

FK-506 is a resistance-modulating agent (RMA) for tumor cells whose multidrug resistance (MDR) involves a P-glycoprotein (Pgp)-mediated anti-cancer drug efflux. The family of FK-506 relatives and derivatives includes analogs which display a whole range of chemosensitizing strengths, from no detectable RMA activity to a complete reversion of the MDR phenotype. Similarly, FK-506 analogs display a whole range of immunosuppressive activities, including inactive ones. FK-506 was compared for RMA activity with 11 FK-506 analogs which were at least 20-fold less active than FK-506 for the inhibition of the bi-directional mixed lymphocyte reaction displayed the whole range of RMA activity. One such strong RMA derivative of FK-506 (SDZ 280-629) was further shown able to restore completely daunomycin retention by highly resistant MDR P388 tumor cells.

Synthesis of new polyoxin derivatives and their activity against chitin synthase from Candida albicans.

Two analogues of L-alanylpolyoxin C with a modified peptide bond were synthesized and tested for inhibition of chitin synthase in Candida albicans. N-Methylation of the peptide bond (compound 13) or the replacement of it by NH2CH2 (compound 9) led to loss of activity in the enzyme assay. A novel analogue (compound 5) of nikkomycin was synthesized from uracil polyoxin C and (2S,3R)-3-hydroxyhomotyrosine, a component of echinocandin C. Despite high activity in the chitin synthase assay, 5 had no inhibitory effect on cells of C. albicans.

Preparation and antibacterial activities of new 1,2,3-diazaborine derivatives and analogues.

1,2-Dihydro-1-hydroxy-2-(organosulfonyl)areno[d] [1,2,3]diazaborines 2 (arene = benzene, naphthalene, thiophene, furan, pyrrole) were synthesized by reaction of (organosulfonyl)hydrazones of arene aldehydes or ketones with tribromoborane in the presence of ferric chloride. The activities of 2 against bacteria in vitro and in vivo (Escherichia coli) were determined and structure-activity relationships are discussed. Included in this study are 2,3-dihydro-1-hydroxy-2-(p-tolylsulfonyl)-1H-2,1-benzazaborole+ ++ (3) and 1-hydroxy-1,2,3,4-tetrahydro-2-(p-tolylsulfonyl)-2,1-benzazabor ine (4) as well as the carbacyclic benzodiazaborine analogue 4-hydroxy-3-(p-tolylsulfonyl)isoquinoline (7). The nature of the active species is briefly discussed.