Sigma-1 ligands: Tic-hydantoin as a key pharmacophore.

Sigma-1 receptors are involved in numerous pathological dysfunctions and the synthesis of selective ligands is of interest. We identified a fused tetrahydroisoquinoline-hydantoin (Tic-hydantoin) structure with high affinity and selectivity for these receptors. We report here our efforts towards the pharmacomodulation of this substructure, the synthesis of 9 analogs with stereochemistry inversion, opening of isoquinoline ring, removal of isoquinoline nitrogen, replacement of isoquinoline by pyridine, of Tic-hydantoin moiety by quinazolinedione heterocycle.

Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine derivatives as CDK inhibitors and cytotoxic agents.

We here report the synthesis and biological evaluation of new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine designed as potential CDK inhibitors. Indole, 5-hydroxyindole, and phenol derivatives were used to generate three substitutions of the pyridine. The resulting skeletons were successively exploited to introduce various dimethylaminoalkyl side chains by Williamson type reactions.

Synthesis of 2,6-diphenylpyrazine derivatives and their DNA binding and cytotoxic properties.

A series of 2,6-diphenylpyrazine derivatives was synthesized from 2,6-dichloropyrazine and 4-methoxyphenylboronic acid using palladium(0) as catalyst in a Suzuki methodology. After deprotection of the hydroxyl, alkylation reactions with different halides afforded compounds 5-8 bearing hydrophilic chains. DNA binding and cytotoxic properties were investigated.

Synthesis of 2,5- and 3,5-diphenylpyridine derivatives for DNA recognition and cytotoxicity.

A series of 2,5- and 3,5-diphenylpyridine derivatives was synthetised in high yields. A versatile chemical strategy allows the design of diphenylpyridines differently substituted with cationic or neutral side chains. The interaction of the molecules with DNA was investigated by biophysical and biochemical methods and an AT-binder (20) was characterised.

Targeting DNA with novel diphenylcarbazoles.

Double-stranded DNA is a therapeutic target for a variety of anticancer and antimicrobial drugs. Noncovalent interactions of small molecules with DNA usually occur via intercalation of planar compounds between adjacent base pairs or minor-groove recognition by extended crescent-shaped ligands. However, the dynamic and flexibility of the DNA platform provide a variety of conformations that can be targeted by structurally diverse compounds.

Synthesis of diphenylcarbazoles as cytotoxic DNA binding agents.

We report the synthesis of a series of novel diphenylcarbazoles designed to interact with DNA. The compounds bearing two or three dimethylaminoalkyloxy side chains were found to bind much more tightly to DNA, preferentially at AT-rich sites, than the corresponding hydroxy compounds. The DNA binding compounds exhibit potent cytotoxic activity toward P388 leukemia cells.