Synthesis and biological evaluation of novel cyclic enediyne compounds related to dynemicin A as antitumor agents.
Novel cyclic enediyne compounds, which are simple functional analogs of dynemicin A (1) having the bicyclo-[7.3.1]tridec-4-ene-2,6-diyne system, were synthesized and evaluated for the DNA-cleaving ability, in vitro cytotoxicity and in vivo antitumor activity. All of the sulfones 19-24, which were equipped with a 2-(arylsulfonyl)-ethoxycarbonyl group or the 2-(methylsulfonyl)ethoxycarbonyl group as a triggering device, showed both potent DNA-cleaving activity and cytotoxicity against various tumor cell lines. However, these compounds were entirely inactive or only slightly active against murine P388 leukemia in mice. On the other hand, the enediyne 2a having a phenyl carbamate moiety as a stable N-protecting group showed effective antitumor activity both in vitro and in vivo. In particular, it exhibited significant antitumor activity against Lewis lung carcinoma in mice. These results show that the character of the carbamate moiety of the cyclic enediynes strikingly affects their biological activities, that is, the sulfonylethyl carbamate moiety is an effective triggering device for both DNA-cleaving activity and cytotoxicity, and the phenyl carbamate moiety is significant for antitumor activity in vivo. As part of a mechanistic study, the reactivities of 2a and 21 were examined under a weakly basic condition (pH 9.3); both compounds failed to give the Bergman cycloaromatization product.
Unno
R
R
Drug Discovery Research Department, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan.
Michishita
H
H
Inagaki
H
H
Baba
Y
Y
Jomori
T
T
Nishikawa
T
T
Isobe
M
M
D000480:Alkynes; D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D004278:DNA, Superhelical / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D053281:Enediynes; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013450:Sulfones / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000480:Alkynes; D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D001643:Bridged Bicyclo Compounds; D002219:Carbamates; D004278:DNA, Superhelical; D053281:Enediynes; D004852:Epoxy Compounds; D013450:Sulfones; C104690:phenyl-9-hydroxy-9-methyl-10,2,10-(epoxymetheno)-2-benz(b)azacyclododeca-5-ene-3,7-diyne-1-carboxylate; C061229:dynemicin A