No abstract

No abstract

A series of phenylthiourea and ethylthiourea derivatives of daunorubicin and its congeners was prepared by reaction of the 3'-amino group of the antibiotic with phenylisothiocyanate or ethylisothiocyanate.S-Methylation yielded 5-methylisothiouronium salts which when reacted with amines resulted in an intramolecular cyclization with the participation of the neighboring 4'-OH group. The structures and predominant conformations of the thiourea derivatives andwere determined by *H and 13C NMR.Cytostatic activities of the thiourea and oxazoline derivatives were compared with the cytostatic activities of TV-methylurea and A'-methyl-TV-nitrosourea containing daunorubicin and its congeners. Carminomycin derivatives were endowedwith the highest cytostatic activity.In the course of a screening program for novel second generation antitumor anthracycline antibiotics of dauftorabicin (1) series, derivatives containing in 3' -position N-methylurea (2) or 7V-methyl-iV-nitrosourea moieties (3) were synthesized1}. In alkaline conditions, 3/-(7V-methyl-ALnitrosoaminocarbonyl)daunorubicin (3a) or related compounds produce 3'-JVr,4'-0-carbonyl derivatives by intramolecular cyclization of intermediate 3-deamino-3'-isocyanato derivativesX).In this paper we report on the preparation of thiourea-containing derivatives of daunorubicin and its analogs which are susceptible to transformations with neighboring 4'-hydroxy group participation. Also, the structure-cytostatic activity relationship among urea and thiourea derivatives of anthracycline antibiotics was investigated. ChemistryDaunorubicin (la), carminomycin (lb), doxorubicin (1c) and 14-pimeloyloxydaunorubicin (ld)1}, upon interaction with phenylisothiocyanate or ethylisothiocyanate in pyridine afforded the corresponding phenylthiourea (5a~5d) of ethylthiourea (6a and 6c) derivatives in 77~99% yield. Previously, 5a was obtained from la and phenylisothiocyanate in chloroform-methanol mixture in a yield of 64%2). S-Methylisothiouronium salts of these compounds7a, 7b and 8a were obtained by alkylation with CH3I in methanol. Usually S-alkylisothiouronium salts easily produce guanidines by the action of amines. Compounds 7 and 8 were selected for their transformation to substituted guanidine derivatives (9). Upon interaction with primary amines (methylamine, n-pentylamine or tris(hydroxymethyl)aminomethane) 7a, 7b and 8a yielded daunorubicino(3',4'-d)oxazoline derivatives (10a, 10b or lla), respectively. The formation of a 5-membered cycle is facilitated as in the case of transformations of Af-methyl-iV-nitrosoaminocarbonylderivatives of daunorubicin (4)1}.We could demonstrate by HPLCthat storage of 5-methylisothiouronium salt 7a during 1-day in

No abstract

1992 nucleic acids nucleic acids U 0700 35 -279 3-Hydroxymethylation of Indoles and Synthesis of Ascorbigens. --(PLIKHTYAK, I. L.; YARTSEVA, I. V.; ALEKSANDROVA, L. G.; PODKHALYUZINA, N. YA.; PREODRAZHENSKAYA, M. N.; Khim.-Farm. Zh. 25 (1991) 6, 57-59; Mosk. khim.-tekhnol. inst. im. Mendeleeva, Moskva; RU) 1