Chiral 6-hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles: novel antitumor DNA monoalkylating agents.
New chiral 1H,3H-pyrrolo[1,2-c]thiazoles were synthesized and screened for their in vitro activity as anti-cancer agents in three human tumor cell lines, colorectal adenocarcinoma, melanoma and breast adenocarcinoma. (R)-6-Hydroxymethyl-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole and the corresponding benzylcarbamate showed selectivity for breast cancer cell lines with IC(50) values of 2.4 microM and 2.2 microM, respectively. The latter also showed significant activity against colorectal adenocarcinoma cancer cell lines (IC(50) = 8.7 microM). In contrast, the 7-hydroxymethyl-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole gave moderate anti-cancer activity. The performance against breast cancer cell lines (IC(50) = 1.0 microM) of a potential bisalkylating agent, a (3R)-6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazole, wasn't significantly different from the one observed for the monoalkylating derivatives indicating that the main mechanism of action may in fact be the monoalkylation process.
Soares
Maria I L
MI
Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal.
Brito
Ana Filipa
AF
Laranjo
Mafalda
M
Abrantes
Ana Margarida
AM
Botelho
M Filomena
MF
Paixão
José A
JA
Beja
Ana Matos
AM
Silva
Manuela Ramos
MR
Pinho E Melo
Teresa M V D
TM
D000230:Adenocarcinoma / Q000188:drug therapy; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D018906:Antineoplastic Agents, Alkylating; D011758:Pyrroles; D013844:Thiazoles; D004247:DNA