Nikolay A. Zefirov

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.

2-Methoxyestradiol and its analogs. Synthesis and structure—antiproliferative activity relationship

Abstract2-Methoxyestradiol is an estradiol metabolite capable of binding to the colchicine domain of the cell protein tubulin. The review systematizes the results of structure—activity studies on 2-methoxyestradiol analogs with various modifications of the A, B, and D rings and describes some synthetic approaches to such analogs. Ways of synthesis of metabolically stable 2-methoxyestradiol via modification of the 3- and 17-hydroxy groups, as well as by introduction of bulky substituents into the 17-position, are discussed. The design of 2-methoxyestradiol analogs lacking steroid fragment is also described.

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.

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.

Heterocycles as classical and nonclassical ring B isosters in combretastatin A-4

The minireview provides a survey of combretastatin A-4 analogs, obtained by isosteric replacement of 3-hydroxy-4-methoxyphenyl ring (ring B) with various heterocyclic systems. The basic synthetic approaches and structure–activity relationships are summarized.

Synthesis and biotests of 2-aryl-5-arylmethylidene-substituted 1,3-oxazol-5(4H)-ones and N-methyl-3,5-dihydro-4H-imidazol-4-ones as combretastatin A-4 analogs

A series of 2-aryl-5-arylmethylidene-1,3-oxazol-5(4H)-ones and 2-aryl-5-arylmethylidene-N-methyl-3,5-dihydro-4H-imidazol-4-ones was synthesized as structural analogs of combret- astatin A-4 (a compound possessing antitumor activity). (5Z)-5-[(4-Methoxyphenyl)methyl-idene]-3-methyl-2-(4-methylphenyl)-3,5-dihydro-4H-imidazol-4-one was found to exhibit the highest cytotoxicity against cells of human A549 lung carcinoma line (EC50 = 6±0.8 μmol L−1).

Molecular design and an attempt to synthesize a conjugate of 2-methoxyestradiol with adamantane

Based on molecular modeling data, 2-adamantyl 8-[(2-methoxyestra-1,3,5(10)-triene-3,17β-diol-6α-yl)amino]octanoate 2d is proposed as a structural analogue of highly cytotoxic N-(8-(adamant-2-yloxi)-8-oxooctanoyl)-N-deacetylcolchycine. Three-step synthesis of adamant-2-yl 8-aminooctanoate 5 is described. Reductive amination of 2-methoxy-6-oxo-17β-estradiol in weakly acidic medium in the presence of compound 5 and NaBH3CN or Na(OAc)3BH results in the product of elimination at the C6–C7 bond of steroid 7 rather than the formation of conjugate 2d.

Synthesis of steroid analogs of tubuloclustin, their cytotoxicity and effect on microtubules of A549 carcinoma cells

Synthesis of analogs of tubuloclustin (N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine (1)) with the colchicine fragment replaced with 2-methoxyestradiol scaffold attached via phenolic hydroxy group was described. Esters 3a–c exhibit moderate cytotoxicity (EC50 = 5–6 μmol L–1) and exert a weak effect on the microtubule network in A549 human lung carcinoma cells similar to the clustering effect of tubuloclustin and its derivatives. Conjugates 6a–c and 7a–c with the phenolic ester bond are low stable and compounds 7a–c are inactive to the microtubules of A549 cells, while compounds 6a–c cause an unusual effect of curling of the microtubules.

Adamantane acid esters with alkoxyaryl alcohols: Synthesis, antiproliferative activity, and influence on microtubule network of tumor cells

Adamantaneacetic and adamantanecarboxylic acid esters containing 3-hydroxy-4-methoxybenzyl, 3,4,5-trimethoxybenzyl, or 5-(hydroxymethyl)-2-methoxyphenyl groups were synthesized as unusual analogs of natural antitumor and anti-tubulin agents combretastatin A-4 and 2-methoxyestradiol. The compounds were found to possess noticeable cytotoxicity to epithelial human carcinoma cell line A549 (EC50 = 4.3—81 μmol L–1). An ability to cause complete depolymerization of microtubule network of A549 cells was demonstrated for 5-(hydroxymethyl)-2-methoxyphenyl adamantan-1-ylacetate (6a) at a concentration of 100 μmol L–1. Ester 6a belongs to a new structural type, which is unusual for the ligands of the tubulin colchicine domain, and is an interesting lead compound for further structural optimization.