O. N. Zefirova

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.

Ligands of the colchicine site of tubulin: A common pharmacophore and new structural classes

Structure-activity relationships for ligands of the colchicine site of tubulin were analyzed based on their common pharmacophore. The role of the elucidation of the three-dimensional structure of the colchicine site of tubulin on the development of studies aimed at the search for the ligands of this site is analyzed.

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.

Targeted Delivery of Drugs Provided by Water-Soluble Polymeric Systems with Low Critical Solution Temperature (LCST

A new approach to the targeted thermally activated transport of chemical agents and physiologically active compounds is reported. The method involves the immobilization of these compounds on a water-soluble polymer with a low critical solution temperature and heating the delivery site above the critical temperature. The approach was illustrated with trypsin immobilized on N-isopropylacrylamide-acrylamide-N-acryloylphthalimide ternary copoly mers.

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 study of NOS-inhibiting activity of 2-N-acylamino-5,6-dihydro-4H-1,3-thiazine

The synthesis and results of in vitro and in vivo testing of 2-N-acetylamino-, 2-N-benzoylamino-,2-N-cyclohexanecarbonylamino-, and 2-N-(1-adamantanecarbonyl)amino-5,6-dihydro-4H-1,3-thiazines for NOS-inhibiting activity have been described.

Application of the bridgehead fragments for the design of conformationally restricted melatonin analogues.

Conformationally constrained analogues of the hormone melatonin with a side chain incorporated into the bicyclic bridgehead core were synthesized based on the homology modeling and molecular docking studies performed for the MT(2) melatonin receptor. The methoxy-indole derivative fused with exo-N-acetamino-substituted bicyclo[2.2.2]octane was found to possess nanomolar MT(2) receptor affinity.

Synthetic Approaches to Physiologically Active Polycyclic Compounds: III. Ritter Reaction with Ketones of the Adamantane and Oxahomoadamantane Series

Some previously unknown acetamino derivatives were synthesized by the Ritter reaction from ketones of the adamantane and oxahomoadamantane series. The presence of a hydroxy group as substituent in adamantan-2-one gives rise to formation of acetamino derivatives as products of replacement of the hydroxy group and transformation of the carbonyl group.

Synthetic Approach to Preparation of Polycyclic Compounds Possessing Physiological Activity: I. Synthesis of 1,4-Disubstituted Adamantanes with Amino Acid Fragment

In the present publication various synthetic procedures are reported for previously unknown 1,4-disubstituted adamantanes, containing in particular in position 1 an amino acid fragment (N-benzoyl-β-alanyloxy group). The procedures developed for modification of functional groups in the adamantane skeleton provide a possibility of synthesis of compounds with potential anticancer activity.