cis-Restricted 3-aminopyrazole analogues of combretastatins: synthesis from plant polyalkoxybenzenes and biological evaluation in the cytotoxicity and phenotypic sea urchin embryo assays.
We have synthesized a series of novel cis-restricted 4,5-polyalkoxydiaryl-3-aminopyrazole analogues of combretastatins via short synthetic sequences using building blocks isolated from dill and parsley seed extracts. The resulting compounds were tested in vivo in the phenotypic sea urchin embryo assay to reveal their antimitotic and antitubulin effects. The most potent aminopyrazole, 14a, altered embryonic cell division at 10 nM concentration, exhibiting microtubule-destabilizing properties. Compounds 12a and 14a displayed pronounced cytotoxicity in the NCI60 anticancer drug screen, with the ability to inhibit growth of multi-drug-resistant cancer cells.
N. D. Zelinsky Institute of Organic Chemistry, RAS , Leninsky Prospect 47, 119991 Moscow, Russian Federation.
Dmitry V
DV
Tsyganov
Leonid D
LD
Konyushkin
Irina B
IB
Karmanova
Sergei I
SI
Firgang
Yuri A
YA
Strelenko
Marina N
MN
Semenova
Alex S
AS
Kiselyov
Victor V
VV
Semenov
D028524:Anethum graveolens / Q000737:chemistry; D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001632:Bibenzyls / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004625:Embryo, Nonmammalian / Q000187:drug effects; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D028528:Petroselinum / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D012617:Sea Urchins / Q000196:embryology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000494:pharmacology
C436945:3-aminopyrazole; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D001632:Bibenzyls; D011720:Pyrazoles; D050257:Tubulin Modulators; C040105:combretastatin