Sulfonyl-Containing Aldophosphamide Analogues as Novel Anticancer Prodrugs Targeted against Cyclophosphamide-Resistant Tumor Cell Lines

Abstract

A series of sulfonyl-group containing analogues of aldophosphamide (Aldo) were synthesized as potential anticancer prodrugs that liberate the cytotoxic phosphoramide mustards (PM, IPM, and tetrakis-PM) via -elimination, a nonenzymatic activation mechanism. Kinetic studies demonstrated that all these compounds spontaneously liberate phosphoramide mustards with half-lives in the range of 0.08-15.2 h under model physiological conditions in 0.08 M phosphate buffer at pH 7.4 and 37°C. Analogous to Aldo, the rates of -elimination in all compounds was enhanced in reconstituted human plasma under same conditions. The compounds were more potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung fibroblasts in vitro (IC 50 ) 1.8-69.1 µM). Several compounds showed excellent in vivo antitumor activity in CD2F1 mice against both P388/0 (Wild) and P388/CPA (CP-resistant) tumor cell lines.

Sulfonyl-Containing Nucleoside Phosphotriesters and Phosphoramidates as Novel Anticancer Prodrugs of 5-Fluoro-2‘-deoxyuridine 5‘-Monophosphate (FdUMP)

“…Several sulfonylethyl-containing phosphotriester and phosphoramidate analogues of FdUMP have been synthesized and examined as novel anticancer nucleotide prodrugs. Consistent with our previous findings in sulfonyl-containing prodrugs of phosphoramide mustard, the rate of β-elimination of sulfonyl pronucleotides was influenced by the substitution on the sulfonylethyl group and the types of leaving group. Compounds 5 and 6 exhibited greater stability than 4 , apparently due to the change of the nature of the leaving groups (e.g., phosphoramidic acid vs phosphoric acid) or the number of sulfonylethyl groups accessible for β-elimination.…”

“…Several nucleotide prodrug (pronucleotide) approaches have been attempted to circumvent the delivery problems of FdUMP. − The major challenge of developing FdUMP prodrugs has been in the selection of a suitable phosphate masking group. Sulfonylethyl groups have been successfully exploited as promoieties for phosphoramidate mustard derivatives. , It is hypothesized that the sulfonylethyl groups may also serve as useful phosphate masking groups in the development of FdUMP prodrugs.

1 Structures of 5-FU, FdU, and FdUMP

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2-(4-Tolylsulfonyl)ethoxymethyl (TEM)—a new 2′-OH protecting group for solid-supported RNA synthesis

“…The reagent, TEM-Cl (5), was synthesized using the strategy shown in Scheme 3: 2-(4-tolylthio)ethanol (2) was synthesized from 4-methylbenzenethiol (1). 30 The thioether 2 was first oxidized to sulfone 3 in 96% yield by 35% hydrogen peroxide in aqueous acetic acid (H 2 O-AcOH, 1 : 1, reflux, 20 min). Then sulfone 3 was treated with a mixture of DMSO, acetic acid and acetic anhydride at room temperature for two days, followed by purification by silica gel column chromatography to give O,S-acetal 4 (74%).…”

Diastereo- and Enantioselective Catalytic Radical Oxysulfonylation of Alkenes in β,γ-Unsaturated Ketoximes

“…The aryl and alkyl sulfone groups, thanks to their unique physicochemical properties, are a kind of important pharmacophores in structure-based drug design and thus, are of great importance in the development of drugs and agrochemicals. [56][57][58][59][60][61][62][63] In addition, enantiomerically enriched b-hydroxysulfone represents a privileged scaffold found in many biologically relevant molecules, such as the anticancer drug bicalutamide and antifungal agents SSY726 and SCH42427. [64][65][66][67][68][69][70][71][72] Nonetheless, their asymmetric construction remains a significant challenge.…”