Venerando Pistarà

Recent advances in small organic molecules as DNA intercalating agents: Synthesis, activity, and modeling

The interaction of small molecules with DNA plays an essential role in many biological processes. As DNA is often the target for majority of anticancer and antibiotic drugs, study about the interaction of drug and DNA has a key role in pharmacology. Moreover, understanding the interactions of small molecules with DNA is of prime significance in the rational design of more powerful and selective anticancer agents. Two of the most important and promising targets in cancer chemotherapy include DNA alkylating agents and DNA intercalators. For these last the DNA recognition is a critical step in their anti-tumor action and the intercalation is not only one kind of the interactions in DNA recognition but also a pivotal step of several clinically used anti-tumor drugs such as anthracyclines, acridines and anthraquinones. To push clinical cancer therapy, the discovery of new DNA intercalators has been considered a practical approach and a number of intercalators have been recently reported. The intercalative binding properties of such molecules can also be harnessed as diagnostic probes for DNA structure in addition to DNA-directed therapeutics. Moreover, the problem of intercalation site formation in the undistorted B-DNA of different length and sequence is matter of tremendous importance in molecular modeling studies and, nowadays, three models of DNA intercalation targets have been proposed that account for the binding features of intercalators. Finally, despite DNA being an important target for several drugs, most of the docking programs are validated only for proteins and their ligands. Therefore, a default protocol to identify DNA binding modes which uses a modified canonical DNA as receptor is needed.

Diastereo- and enantioselective synthesis of N,O-nucleosides

Abstract The diastereo- and enantioselective synthesis of α- and β-3′-hydroxymethyl-N,O-nucleosides is described, based on the 1,3-dipolar cycloaddition of a N-glycosyl nitrone. Two approaches have been evaluated: the one-step procedure, which uses vinyl nucleobases, showed a better stereoselectivity towards β-nucleosides.

Diastereoselective and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides

Abstract A diastereo- and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides has been designed by the strategy of the 1,3-dipolar cycloaddition reaction of a Vasella-type nitrone. The reaction leads to (1′ R )- and (1′ S )-4′-aza analogues of 2′,3′-dideoxythimidine and fluorouridine, in enantiomerically pure forms.

An asymmetric approach to pyrrolidinone and pyrrolizidinone systems by intramolecular oxime-olefin cycloaddition

Abstract Homochiral functionalized pyrrolidinone and pyrrolizidinone systems have been achieved by stereoselective intramolecular oxime-olefin cycloaddition starting from homochiral amino acids, and by subsequent reduction of the obtained fused isoxazolidines.

Modified nucleosides. A general and diastereoselective approach to N,O-psiconucleosides

An efficient reaction route towards the new class of N,O-psiconucleosides has been designed, based on the 1,3-dipolar cycloaddition of C-[(tert-butyldiphenylsilyl)oxy]methyl-N-methyl nitrone with ethyl 2-acetyloxyacrylate, followed by nucleosidation. The process has been successfully applied to all pyrimidine and purine nucleobases.

A new highly diastereoselective synthesis of epi-inositol from d-galactose

Abstract The inosose derivative 3 was obtained with high stereoselectivity by intramolecular aldol condensation of the aldohexos-5-ulose derivative 2 , and it was selectively reduced and debenzylated to give epi -inositol in high yield. The stereochemistry and the preferred conformations of compounds 3 – 7 were determined through 1D and 2D NMR experiments.

Intramolecular aldol cyclization of L-lyxo-hexos-5-ulose derivatives: a new diastereoselective synthesis of D-chiro-inositol.

Abstract The DBU-promoted intramolecular aldol condensation of two partially protected l - lyxo -hexos-5-ulose derivatives ( 8 and 9 ), in turn obtained starting from methyl β- d -galactopyranoside, takes place with fairly good yield and complete diastereoselectivity to give 2 l -(2,3,6/4,5)-pentahydroxycyclohexanone derivatives, 10 and 11 . The stereoselective reduction of inosose 10 with sodium triacetoxyborohydride leads, after catalytic debenzylation, to d - chiro -inositol ( 1 ), while the sodium borohydride reduction furnishes, with opposite stereoselectivity, a derivative of allo -inositol.

Diastereoselective Synthesis ofN,O-Psiconucleosides, a New Class of Modified Nucleosides

Anomeric α- and β-N,O-psiconucleosides were prepared by 1,3-dipolar cycloaddition of C-ethoxycarbonyl N-methyl nitrone with ethyl 2-acetyloxyacrylate, followed by Vorbruggen nucleosidation. The synthetic scheme has been applied to all purine and pyrimidine nucleobases. Nucleosidation can proceed under kinetic and under thermodynamic control; under thermodynamic control conditions only β-nucleosides are obtained for pyrimidine derivatives and α-nucleosides for purine derivatives. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Stereoselective synthesis of isoxazole and pyrazole annulated sultams via intramolecular 1,3-dipolar cycloaddition reactions

Abstract Functionalized isothiazoloisoxazole-4,4-dioxide, pyrazoloisothiazole-1,1-dioxide, [1,2]thiazinoisoxazole-4,4-dioxide and benzo[1,2]thiazinoisoxazole-4,4-dioxide systems have been obtained by intramolecular 1,3-dipolar cycloaddition, starting from substituted α- and β-sulfonamides.

Cycloaddition of benzonitrile oxide to pyridazine, pyrimidine and pyrazine

Abstract Cycloaddition of benzonitrile oxide to pyridazine affords an isolable mono-cycloadduct. In cycloadditions to pyrimidine and pyrazine the primary mono-cycloadducts are labile intermediates which undergo further cycloaddition affording isolable bis- and tris-cycloadducts.