Synthesis and Anticancer Activity of (R,S)‐9‐(2,3‐Dihydro‐1,4‐Benzoxathiin‐3‐ylmethyl)‐9H‐Purines

Abstract

A series of eleven 2- and 6-substituted (R,S)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purine derivatives was obtained by applying a standard Mitsunobu protocol that led to a six-membered ring contraction from (R,S)-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol via an episulfonium intermediate. The signal approximately delta=151 ppm, which corresponds to the C4' carbon atom, is unequivocal proof of the N9' regioisomer. The potential of the target molecules as anticancer agents is reflected in their activity against the MCF-7 cancer cell line. The most active compounds have IC(50) values of (6.18+/-1.70) and (8.97+/-0.83) microM. The results indicate that the anticancer activity for the most active compounds is correlated with their capacity to induce apoptosis.

Synthesis and Anticancer Activity of the (R,S)‐Benzofused 1,5‐Oxathiepine Moiety Tethered to Purines through Alkylidenoxy Linkers

“…Derivatives 18 and 19 (with the propylenoxy linker) are more active than their ethylenoxy-linked counterparts (compounds 14 and 15), whereas compounds 13 and 17 are equipotent, and the two adenine derivatives (compounds 16 and 20) are inactive. In comparing the three most active compounds of both the six-membered (compounds 2-4) [9] and seven-membered (compounds 17-19) series, the following conclusions can be drawn: 1) Both series follow the same trend in potency from a qualitative point of view: 6-bromo (19 and 4) > 2,6-dichloro (18 and 3) > 6-chloro (17 and 2). 2) Compounds 18 (IC 50 = 6.67 AE 0.06 mm) and 19 (IC 50 = 5.14 AE 0.06 mm), which belong to the seven-membered ring series, are more active than the corresponding compounds of the sixmembered series [3 (IC 50 = 8.97 AE 0.83 mm) and 4 (IC 50 = 6.18 AE 1.70 mm)].…”

“…[9] The subsequent alkylation of 1 with 2-bromoethanol or 3-bromopropanol gave 21 and 22 (Scheme 2). The alkoxide salt of 1 reacts with 2-bromoethanol or 3-bromopropanol to produce the ethers 21 and 22 by an S N 2 mechanism.…”

“…However, this procedure led to a sixmembered ring contraction from a secondary alcohol in a seven-membered cycle (compound 1) under microwave heating to produce compounds 2-12 (Scheme 1). [9] The course of the reaction followed a different pathway because the sulfur atom competed as an alternative nucleophile, which implied the formation of an episulfonium ion intermediate. [9] Several seven-membered O,N-acetals with oxygen and/or sulfur atoms at the respective 1-and 4-positions have been reported with interesting antiproliferative activities.…”

“…[9] The course of the reaction followed a different pathway because the sulfur atom competed as an alternative nucleophile, which implied the formation of an episulfonium ion intermediate. [9] Several seven-membered O,N-acetals with oxygen and/or sulfur atoms at the respective 1-and 4-positions have been reported with interesting antiproliferative activities. [10] In the present work the secondary hydroxy group was transformed into hydroxyethylenoxy or hydroxypropylenoxy fragments, allowing separation of the newly generated primary hydroxy group from the seven-membered ring to avoid sulfur neighboring group participation and concomitant ring contraction to a six-membered cycle.…”

Apoptosis as a Therapeutic Target in Cancer and Cancer Stem Cells: Novel Strategies and Futures Perspectives

“…Moreover, these strategies overcome the adverse effects associated with cytotoxic drugs and increase their anti-cancer activity. Novel antitumour drugs have been synthesised such as 5-FU O,N-acetals and benzo-fused seven-membered O,N-acetal in which the 5-FU moiety was changed for the naturallyoccurring pyrimidine base uracil, which induced cell cycle-mediated apoptosis in breast and colon cancer cells [16,17,18,19]. The mechanism of action of these drugs was mainly centred on positive apoptosis regulatory pathway genes, and the repression of genes involved in carcinogenesis, proliferation and tumour invasion.…”