title: Synthesis and cytotoxic activity of a new group of heterocyclic analogues of the combretastatins.
abstract: A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6-8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9-11. The methoxy-, hydroxyl- and formyl- substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.
authors: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, Novosibirsk 630090, Russia. mond_05@list.ru.
authors: Alla V
authors: AV
authors: Lipeeva
authors: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, Novosibirsk 630090, Russia. schultz@nioch.nsc.ru.
authors: Elvira E
authors: EE
authors: Shults
authors: Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, Novosibirsk 630090, Russia. mmsh@nioch.nsc.ru.
authors: Makhmut M
authors: MM
authors: Shakirov
authors: Medicinal Department, Novosibirsk State University, Pirogova St. 2, Novosibirsk 630090, Russia. miha.pokrovsky@gmail.com.
authors: Mikhail A
authors: MA
authors: Pokrovsky
authors: Medicinal Department, Novosibirsk State University, Pirogova St. 2, Novosibirsk 630090, Russia. decan@medf.nsu.ru.
authors: Andrey G
authors: AG
authors: Pokrovsky
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005363:Ficusin / Q000737:chemistry / Q000494:pharmacology; D011564:Furocoumarins / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D003374:Coumarins; D011564:Furocoumarins; D013267:Stilbenes; D050257:Tubulin Modulators; C040105:combretastatin; C058728:fosbretabulin; D005363:Ficusin; C429130:oreoselone