Retinoic acid conjugates as potential antitumor agents: synthesis and biological activity of conjugates with Ara-A, Ara-C, 3(2H)-furanone, and aniline mustard moieties.
In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to behave as a covalent carrier for cytotoxic entities, conjugates of retinoic acid with a few representative molecules, being important examples of antitumor pharmacophores (i.e., nucleoside analogues and alkylating agents), have been synthesized and tested for their cytostatic and differentiating activity. All compounds were stable to in vitro hydrolysis in human plasma and more lipophilic than the parent compounds, thus consenting enhanced uptake into the cells. Among the nucleoside analogues the Ara-C derivatives 3 and 6 and the Ara-A derivative 7 proved the most cytostatic (IC50 < 0.32 microgram/mL) resulting from 25- to > 144-fold more active (Ara-A derivatives) or at least as equally active (Ara-C derivatives) as compared to the parent nucleosides. Compound 3, endowed with a highly lipophilic silyl moiety at the 3' and 5' positions, showed the highest differentiating activity (54% and 44% differentiated HL-60 cells at 0.2 and 0.05 microgram/mL respectively). With regard to the retinoic acid conjugates of alkylating agents, compound 10 was the most cytostatic agent (IC50 < 0.32 microgram/mL) and the most potent differentiating agent (33-34% at 0.32 and 0.08 microgram/mL). These structures may also be regarded as analogs of either retinoic acid or the cytotoxic compound.
Manfredini
S
S
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Simoni
D
D
Ferroni
R
R
Bazzanini
R
R
Vertuani
S
S
Hatse
S
S
Balzarini
J
J
De Clercq
E
E
D000816:Aniline Mustard / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D003561:Cytarabine / Q000138:chemical synthesis / Q000494:pharmacology; D004337:Drug Carriers; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology*; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014212:Tretinoin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D014740:Vidarabine / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D004337:Drug Carriers; D005663:Furans; D009705:Nucleosides; D003561:Cytarabine; D014212:Tretinoin; D000816:Aniline Mustard; D014740:Vidarabine