E. V. Nurieva

Taxol: Synthesis, bioactive conformations, and structure-activity relationships in its analogs

The review describes the syntheses and probable biologically active conformations of taxol, a natural antitumor agent, and systematizes published data on the structure-activity relations in the series of taxol analogs.

Synthesis and SAR requirements of adamantane–colchicine conjugates with both microtubule depolymerizing and tubulin clustering activities

A series of analogues of conjugate 1, combining an adamantane-based paclitaxel (taxol) mimetic with colchicine was synthesized and tested for cytotoxicity in a cell-based assay with the human lung carcinoma cell line A549. The most active compounds (10 EC(50) 2 ± 1.0 nM, 23 EC(50) 6 ± 1.4 nM, 26 EC(50) 5 ± 1.8 nM, 28 EC(50) 11 ± 1.7 nM, 30 EC(50) 4.8 ± 0.5 nM) were found to interfere with the microtubule dynamics in an interesting manner. Treatment of the cells with these compounds promoted disassembly of microtubules followed by the formation of stable tubulin clusters. Structure-activity relationships for the analogues of 23 revealed the sensitivity of both cytotoxicity and tubulin clustering ability to the linker length. The presence of adamantane (or another bulky hydrophobic and non-aromatic moiety) in 23 was found to play an important role in the formation of tubulin clusters. Structural requirements for optimal activity have been partially explained by molecular modeling.

Design, synthesis, and bioactivity of putative tubulin ligands with adamantane core

Several adamantane-based taxol mimetics were synthesized and found to be cytotoxic at micromolar concentrations and to cause tubulin aggregation. The extent of the aggregation is maximal for N-benzoyl-(2R,3S)-phenylisoseryloxyadamantane (5) and is very sensitive to the structural modifications. A hybrid compound (15), combining adamantane-based taxol mimetic with colchicine was synthesized and found to possess both microtubule depolymerizing and microtubule bundling activities in A549 human lung carcinoma cells.

Unusual Tubulin-Clustering Ability of Specifically C7-Modified Colchicine Analogues

Highly cytotoxic C7-modified colchicine analogues, exemplified by tubuloclustin, promote microtubule disassembly followed by the formation of very stable tubulin clusters, both in vitro and in cells. The proposed mechanism of action of tubuloclustin and its analogues, beyond that of colchicine, includes additional specific interactions with the α-tubulin subunit.

Synthesis and biological testing of tubuloclustin analogs containing alicyclic groups and 2-methoxyestradiol moiety

A number of analogs of tubuloclustin, N-[7-(2-adamantyloxy)-7-oxoheptanoyl]-N-deacetylcolchicine, were obtained. In these analogs, the colchicine moiety is formally replaced by the cyclohexane, adamantane, and 2-methoxyestradiol moieties (the steroid is attached through the hydroxy group at the C(17) atom). MTT assays revealed that the conjugates obtained are much less cytotoxic against A549 lung carcinoma cells than the lead compound.

Antiproliferative Activity of Tubuloclustin and its Steroid Analogs

Daily administration of tubuloclustin (1 mg/kg, 5 d, i.p.) to BDF1 mice with i.p. transplanted P388 leukemia extended statistically significantly by 45% their life spans compared with those of untreated controls (17 vs. 11.7 ± 3 d). The possibility in principle of preparing 2-methoxyestradiol analogs with a linker bonded through a steroid C6 ester was demonstrated. However, the resulting conjugates IIa and IIb were unstable with respect to a strong tendency for elimination from the C6–C7 bond. This may have been the reason for their low cytotoxicity in the MTT assay on A549 cell culture (IC50 > 10 μM). It was concluded that conjugates of higher stability must be synthesized as potential antitumor agents.

Synthetic Approaches to Physiologically Active Polycyclic Compounds: VI. Synthesis of 1-[(2R,3S)-N-Benzoyl-phenylisoseryloxy]-4,4-dimethyladamantane

A convenient procedure was proposed for the synthesis of 4,4-dimethyladamantan-1-ol from 2-adamantanone. Esterification of the product with protected amino acid gave 1-[(2R, 3S)-N-benzoylphenyl-isoseryloxy]-4,4-dimethyladamantane.

Synthesis and bioassay of benzimidazole conjugates with adamantane

The synthesis of 2-adamantyl-6-[(1H-benzimidazol-1-ylcarbonyl)amino]hexanoate and 2-adamantyl-7-(1H-benzimidazol-1-yl)-7-oxo-heptanoate, and the results of their cytotoxicity assay against human lung carcinoma cells A549 are presented in the paper. The impossibility of adding 5-(2-adamantyloxycarbonyl)pentyl isocyanate to nocodazole under various conditions was shown.

Synthesis and antiproliferative activity of combretastatin derivatives with adamantane fragment

The work describes the synthesis of 2-adamantyl 7-[(2-{[(2E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)prop-2-enoyl]amino}ethyl)amino]-7-oxoheptanoate and 7-[(2-{[(2E)-2-(3,4-dimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enoyl]amino}ethyl)amino]-7-oxoheptanoate. The latter compound exhibits moderate cytotoxicity (EC50 = 4.8 μmol L–1) against the human epithelial lung carcinoma cells A549.

Synthesis of compounds with potential antitumor activity: IV. Modification of lupinine and menthol by the taxol amino acid moiety

The synthesis and the results of biological testing of novel N-benzoylphenylisoserine-modified L-lupinine and L-menthol are reported.