Search

A series of l -lysine-conjugated pyridophenoxazinones 2–5 and 2′-5′ were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic cell lines. 2 and 5 were the most active compounds with IC50 values in the submicromolar range. UV–vis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 5′-GC-3′ base pairs with the carboxamide side chain lying into major groove. Charge-transfer contribution to the complex stability, evaluated by ab initio calculations, was found to correlate with cytotoxicity. Relaxation and cleavage assays showed that 2 and 5 selectively target Topo IIα over Topo IIβ and stimulate the formation of covalent Topo II–DNA complexes, functioning as poisons. Moreover, compound 5 induced DNA damage and arrested MCF-7 cells at the G2/M phase. Altogether, the work provides interesting structure-activity relationships in the pyridophenoxazinone- l -lysine conjugate series and identifies 5 as a promising candidate for further in vivo evaluation.

We report the ready asymmetric synthesis of nucleoside analogues containing a 1,3-dithiolane ring that mimics the sugar moiety of natural nucleosides. The synthesis is accomplished in three main steps from benzoyloxyethanal 1,3-dithiolane, the key step being its conversion into a chiral monosulfoxide by a modified Sharpless sulfo-oxygenation reaction. The nucleoside analogues were obtained in good overall yields and with excellent enantiomeric excesses. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

In a recent paper2 we have reported the design and synthesis of 3-C-lithiated 5,6-dihydro-1,4-dithiin-2-yl[(4-methoxybenzyl)oxy]methane (1) which can be utilized as an allylic alcohol anion equivalent and leads to three-carbon elongations of various electrophiles by introduction of a fully protected hydroxypropenyl moiety. The latter contains a double bond, which can be unravelled to the cis configuration by diastereoselective removal3 of the dimethylene-disulfur bridge, as well as a protected primary hydroxyl group that, depending on the deprotection conditions used (DDQ/NaBH4 or DDQ), may either lead to the free allylic alcohol or to an α,β-unsaturated aldehyde.

A new high yielding coupling reaction of C-2 monosubstituted 5,6-dihydro-1,4-dithiins with aldehydes is reported. In this way allylic alcohols having the cis-substituted double bond tied up by a sulfur-containing ring can be readily prepared. Subsequent stereoselective sulfur removal then affords allylic alcohols with cis-configurated double bond.

N-Acetyl-1,3-thiazolidine derivatives of cyclohexanones, when treated with a threefold excess N-bromosuccinimide in anhydrous chloroform at room temperature, smoothly afford N-acetyl-2,3-dihydro-1,4-benzothiazines. This represents the first general route to such heterocyclic system in one step from aliphatic precursors. The synthesis of optically active N-acetyl-2,3-dihydro-1,4-benzothiazines is also reported

Perbenzylated 1,7-dioxaspiro[5,5]undec-4-ene derivatives of sugars are obtained in three steps, starting from fully protected glycono-1,5-lactones. The procedure is based on the attack of a lithiated dithiinyl reagent (6) on the starting δ-glyconolactone. The C-glycosidation leads to the sole thermodynamically more stable α-hemiacetal derivative, the spirocyclization of which is then accomplished with BF3·Et2O. The fully protected unsaturated spiroacetals can be smoothly desulfurized for the purpose of any further elaborations of the free double bond. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

A new reagent, based on a 5,6-dihydro-1,4-dithiin heterocyclic system1, has been devised and conveniently used for 3 carbon elongations of various electrophiles. In fact, it acts as either a propenyl alcohol or an acrolein anion equivalent, introducing into the new molecule a moiety consisting of fully protected double bond and allylic oxygen.