Design, synthesis, cytotoxic properties and preliminary DNA sequencing evaluation of CPI--N-methylpyrrole hybrids. Enhancing effect of a trans double bond linker and role of the terminal amide functionality on cytotoxic potency.
In an approach to the design and exploration of the properties of cyclopropylindole (CPI)-lexitropsin conjugates as potential anticancer agents. CPI--N-methylpyrroles of two separate classes have been synthesized and characterized. These comprise structures (i) in which the N-methylpyrrole moiety bears amide groups of different sizes and (ii) in which both flexible and rigid linkers are introduced between the CPI and N-methylpyrrole units. The extent and the relative rates of DNA cleavage following alkylation and thermal treatment by these CPI conjugates were determined by an agarose gel mobility shift assay. The DNA sequence preferences of the seven new agents were also determined in a preliminary study by high-resolution polyacrylamide gel electrophoresis and contrasted with that of CC-1065. The CPI--N-methylpyrrole agents avoid the major alkylation sites of CC-1065, but all alkylate the minor CC-1065 site of 5'AATA and exhibit a consensus sequence of 5'-N.A/T.A/T.A. The cytotoxicities of these compounds were determined against KB human tumor cells in vitro. Compound 6, bearing a 4-butyramide group in the N-methylpyrrole, is 100 times more potent that 7 which lacks an amide group, while 10 which bears a rigid trans double bond linker is 1000 times more potent than its flexible ethyl-linked counterpart.
Wang
Y
Y
Department of Chemistry, University of Alberta, Edmonton, Canada.
Gupta
R
R
Huang
L
L
Luo
W
W
Lown
J W
JW
D000477:Alkylating Agents / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D004249:DNA Damage; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007933:Leucomycins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D011758:Pyrroles; C018782:CC 1065