Synthesis and antiproliferative activity of benzyl and phenethyl analogs of makaluvamines.
Analogs of marine alkaloid, makaluvamine, bearing substituted benzyl and substituted phenethyl side chains have been synthesized and their antiproliferative activities have been evaluated. 4-Methyl, 4-chloro, and 4-fluoro substituted benzyl analogs possessed pronounced antiproliferative effects on the breast cancer cell line, MCF-7 at IC(50) values of 2.3 microM, 1.8 microM, and 2.8 microM, respectively. 4-Methyl, 4-chloro, and 3,4-methylenedioxy derivatives showed the best activity against MCF-7 among the phenethyl analogs with IC(50) values of 2.3 microM, 2.8 microM, and 2.4muM, respectively. In general, methoxy substitutions resulted in slight loss in activity in both benzyl and phenethyl series. Benzyl, 4-fluorobenzyl, 3,4-dimethoxyphenethyl, and 3,4-methylenedioxyphenethyl analogs were tested by NCI in their 60 cell lines in vitro human cancer cell screen. All four compounds showed excellent inhibition against several tested cancer cell lines. Benzyl and 4-fluorobenzyl analogs were relatively more active than 3,4-dimethoxy phenethyl and 3,4-methylenedioxy phenethyl analogs. In NCI assays, the best LogGI(50) values were shown by the fluorobenzyl analog against the renal cancer cell line RXF-393 (<-8.0M) and dimethoxy phenethyl analog against the CNS cancer cell line, SF-268 (<-8.0M). The best LogLC(50) value was shown by the fluorobenzyl analog against the breast cancer cell line MCF-7 (-6.01 M).
Shinkre
Bidhan A
BA
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA.
Raisch
Kevin P
KP
Fan
Liming
L
Velu
Sadanandan E
SE
D001554:Benzene / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C550613:7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one; D011758:Pyrroles; D015363:Quinolones; D011809:Quinones; D001554:Benzene