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

Abstract

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.

Chemical immobilization of retinoic acid within poly(ε‐caprolactone) nanoparticles based on drug–polymer bioconjugates

“…This comes as no surprise because much literature has reported the conjugation reaction using retinoids without conformational changes. [27][28][29][30] Their conformation is known to be sensitive to high temperature and light, which are not involved in our experimental conditions. 31,32 From the 1 H-NMR spectrum of the RA-PCL 10 conjugates, it was possible to determine the conjugation efficiency and the conjugation molar ratio by using the relative peak intensity ratio of CH 3 -protons of RA (1, ␦ ϭ 1.05 ppm) to -CH 2 -protons of PCL 10 (5, ␦ ϭ 4.06 ppm).…”

Enzymatic Synthesis of 2′-O-acyl Prodrugs of 1-(β-D-arabinofuranosyl)-5(E)-(2-bromovinyl)uracil and of 2′-O-acyl-araU, -araC and -araA

“…Thus, a slow release of BV-araU inside cells from prodrugs, which occurs after infection with VZV, would improve its antiviral potential and suggest these compounds as possible candidates for in vivo testing. Indeed, we have very recently reported the improved cytostatic activity of a 2'-retinoyl ester prodrug of araA, which was also remarkably stable (tl/2 »360 min) toward plasma esterases (Manfredini et al, 1997).…”

“…Thus, ester prodrugs at this position will need previous hydrolysis by esterases in order to express, after incorporation into cells, their antiviral potential. In contrast, conjugation with alkyl esters to positions other than 5' might permit phosphorylation of the conjugates by cellular kinase (Manfredini et al, 1997). Indeed, Kano et al (1994) showed that 5'-0-acyl derivatives of BV-araU were unstable in an aqueous solution, resulting in spontaneous conversion of 10 to 20% of the derivatives to BV-araU at 3TC within several hours, and these prodrugs easily gave BV-araU after oral administration into mice by deacylation.…”

Simple synthesis of some new heterocyclic derivatives incorporation coumarin -2-one moiety

“…Many compounds which contain the coumarin moiety exhibit useful and diverse pharmaceutical and biological activities, often depending on the substituents they bear in the parent benzopyran moiety (Musa et al, 2011,Borah et al, 2012 and, there has been a growing interest in their synthesis (EL-Ansary et al, 1992). Some of these coumarin derivatives have been found useful in photochemotherapy, antitumor (Manfredini et al, 1997), anti -HIV therapy (Wattenberg et al, 1979;Kashman et al, 1992) as CNS-stimulants (Mckee et al, 1996), antibacterial (Anjum et al, 2011;De Souza et al, 2005;Behrami, 2014) anticoagulants (Jung and Park, 1999;Barker et al, 1971;Greaves 2005), antifungal (Montagner, 2008: De Araujo et al, 2013, antioxidant (Mazzone et al, 2015) agents and as dyes (Raboin et al, 2000) (all references in text need correction, use et al form instead of number). Natural, semi-synthetic and synthetic coumarins are useful substances in drug research (Karatzas, 2014).…”