| Abstract
| - In a dual targeting approach, to explore the ability oftretinoin (all-trans-retinoic acid) to behaveas a covalent carrier for cytotoxic entities, conjugates of retinoicacid with a few representativemolecules, being important examples of antitumor pharmacophores (i.e.,nucleoside analoguesand alkylating agents), have been synthesized and tested for theircytostatic and differentiatingactivity. All compounds were stable to in vitrohydrolysis in human plasma and more lipophilicthan the parent compounds, thus consenting enhanced uptake into thecells. Among thenucleoside analogues the Ara-C derivatives 3 and6 and the Ara-A derivative 7 provedthemost cytostatic (IC50< 0.32 μg/mL) resulting from 25-to >144-fold more active (Ara-Aderivatives) or at least as equally active (Ara-C derivatives) ascompared to the parentnucleosides. Compound 3, endowed with a highlylipophilic silyl moiety at the 3‘ and 5‘positions, showed the highest differentiating activity (54% and 44%differentiated HL-60 cellsat 0.2 and 0.05 μg/mL respectively). With regard to the retinoicacid conjugates of alkylatingagents, compound 10 was the most cytostatic agent(IC50< 0.32 μg/mL) and the most potentdifferentiating agent (33−34% at 0.32 and 0.08 μg/mL). Thesestructures may also be regardedas analogs of either retinoic acid or the cytotoxiccompound.
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