Synthesis and screening of 6-alkoxy purine analogs as cell type-selective apoptotic inducers in Jurkat cells.

Purines are ubiquitous structures in cell biology involved in a multitude of cellular processes, because of which substituted purines and analogs are considered excellent scaffolds in drug design. In this study, we explored the key structural features of a purine-based proapoptotic hit, 8-tert-butyl-9-phenyl-6-benzyloxy-9H-purine (1), by setting up a library of 6-alkoxy purines with the aim of elucidating the structural requirements that govern its biological activity and to study the cell selectivity of this chemotype. This was done by a phenotypic screening approach based on cell cycle analysis of a panel of six human cancer cell lines, including T cell leukemia Jurkat cells.

Synthesis of 6,8,9 poly-substituted purine analogue libraries as pro-apoptotic inducers of human leukemic lymphocytes and DAPK-1 inhibitors.

A 18-member library of 6,8,9-poly-substituted purines was prepared from pyrimidines, primary alcohols, and N,N-dimethylamides under basic conditions via a novel one-pot synthetic pathway controlled by amide sizes and the novel analogues were tested against two leukemia cell lines: Jurkat (acute T cell leukemia) and K562 (chronic erythroleukemia) cells. Compounds having a benzoxy group at C6 position of the aromatic ring exhibited antiproliferative activity in Jurkat cells whereas all compounds induced a lower effect on K562 cells. Analysis of cell cycle, Annexin-V staining, and cleavage of initiator caspases assays showed that the active purine analogues induce cell death by apoptosis.

Reduction of different electron-poor N-heteroarylhydrazines in strong basic conditions.

The first application of the Wolff-Kishner reduction methodology to electron-poor heteroaromatic compounds is reported. Hydrazino-containing heterocycles with hydrazone-type tautomery have been reduced under basic conditions. This novel chemistry was successfully applied to mono-dehalogenate a number of electron-poor heterocycles in a regioselective manner.

Regioselective one-pot synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines. Reactivity of aliphatic and aromatic hydrazides.

[reaction: see text] The one-pot synthesis of new 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines has been achieved. Hydrazides regioselectively reacted as nucleophiles with the 3-chloro substituent of 2,3-dichloropyrido[2,3-b]pyrazine. An intramolecular cyclization afforded the tricycle nonxanthine adenosine receptor antagonists.

Synthesis and biological evaluation of novel N6-[4-(substituted)sulfonamidophenylcarbamoyl]adenosine-5'-uronamides as A3 adenosine receptor agonists.

A new series of 1-deoxy-1-[(6-(4-(substituted-aminosulfonyl)phenyl)amino)carbonylamino-9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamides (83-102) have been synthesized and tested at the human A3 adenosine receptor subtype. All the derivatives described in this work displayed affinity versus this receptor in the nanomolar range and good selectivity versus A1 adenosine receptor subtype, confirming that the p-sulfonamido moiety positively affected the activity of the molecules. The best substituents at the sulfonamido nucleus were found to be small alkyl groups, like methyl, isopropyl, ethyl, or allyl moieties (compounds 96-100), whereas monosubstitution at the amino group led to a decrease in A3 affinity values.

Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A.

The design, synthesis, characterization, DNA binding properties, and cytotoxic activity of a novel series of hybrids, namely, a molecular combination of the natural antibiotic distamycin A and the antineoplastic agent uramustine, are reported, and the structure-activity relationships are discussed. This homologous series 29-34 consisted of the minor groove binder distamycin A joined to uramustine (uracil mustard) by suitable aliphatic carboxylic acid moieties containing a flexible polymethylene chain that is variable in length [(CH(2))(n)(), where n = 1-6). All the hybrid compounds in this series exhibit enhanced activity compared to both distamycin A and uramustine derivatives 22-27 used for conjugation, giving IC(50) values in the range 7.