Chemical modification of hitachimycin. II. Synthesis and antitumor activities of carbonate derivatives.

Abstract

Several carbonate derivatives of hitachimycin have been synthesized and evaluated their activities including antibacterial, cytocidal against HeLacells and in vivo antitumor against Sarcoma180. Some of these derivatives showed higher antitumor activity than hitachimycin. Amongthe derivatives, ll,15-di-O-methoxycarbonymitachimycin (2), ll,15-di-Oethoxycarbonylhitachimycin (3) and 15-0-methoxycarbonylhitachimycin (9) were most effective in in vivo assay.Hitachimycin (l)1) »nt is a macrocyclic lactam antibiotic isolated from the culture broth of actinomyces strain KM-4927, which shows antitumor3), antibacterial and antiprotozoal activities. Hitachimycin has an unique 19-membered ring lactam structure including trienamide and 1,3-diketone moieties0. The mode of action of hitachimycin and combined effect with bleomycin has been reported by Komiyama et al.*>5\ Since hitachimycin is hardly soluble in water and other organic solvents, it is difficult to utilize the drug for in vivo evaluation. In the course of the chemical modification of hitachimycin to obtain highly soluble and highly active derivatives, 1 1 and 15-0-acyl derivatives have been synthesized and some of them showed superior antitumor effect in vivo, as reported in a previous paper6). In this paper, we describe the synthesis of carbonate derivatives of hitachimycin and their in vivo antitumor activities against Sarcoma 1 80. SynthesisHitachimycin (1) has two hydroxy groups at the C-ll and C-15 positions in its molecule, the 1 1-hydroxy group being an enol of /3-diketone. Treatment of 1 with several alkyl chloroformate such as methyl70 , ethyl, propyl, «-butyl, iso-butyl, 2,2,2-trichloroethyl8) and vinyl chloroformate9) , in pyridine at room temperature gave the ll,15-dicarbonates (2~8), respectively. In the 13C NMRspectra of these carbonates (2~8), a paired signals assignable to carbonyl carbon of each carbonate group (3 154.9~156.2) and corresponded alkyl carbons were observed. Furthermore, up field shift (J 29.3m Hitachimycin was identified with stubomycin by their physico-chemical properties but the production strain of each compoundwas different2).

Mutational Biosynthesis of Hitachimycin Analogs Controlled by the β-Amino Acid–Selective Adenylation Enzyme HitB

“…Hitachimycin (also known as stubomycin; H-1 in Scheme ) is a macrolactam antibiotic with an ( S )-β-phenylalanine ( 1 , β-Phe) at the starter position of its polyketide skeleton. − Hitachimycin was originally isolated from Streptomyces scabrisporus KM-4927 (JCM 11712) and shows antimicrobial, antiprotozoal, and antitumor activities. ,− Hitachimycin can also inhibit yeast plasma membrane ATPase 1 ( Sc Pma1p), indicating its potential utility in the development of novel antifungal therapies with unique mechanisms of action . While the O-11 and O-15 positions of hitachimycin have been chemically modified, most of the derivatives showed weaker biological activity than the original molecule. − Total synthesis of hitachimycin has also been accomplished. , However, modifications at positions other than O-11 and O-15 have not been reported, presumably because of the difficulty of modifying the core polyketide skeleton of hitachimycin, and particularly the ( S )-β-Phe moiety.…”