Abstract
3,5-Bis(arylidene)-N-substituted-4-oxo-piperidine-1-carboxamides 24–51 were synthesized as curcumin mimics in a facile pathway through reaction of 3,5-bis(arylidene)-4-piperidones with the appropriate isocyanate in the presence of triethylamine. The 3E,5E′-stereochemical configuration was conclusively supported by single crystal X-ray studies of compounds 25 and 34. Most of the synthesized piperidinecarboxamides showed high anti-proliferative properties with potency higher than that of 5-fluorouracil (clinically approved drug against colon, breast and skin cancers) through in vitro MTT bio-assay. Some of them revealed anti-proliferative properties at sub-micromolar values (IC50 = 0.56–0.70 μM for compounds 29, 30 and 34–38 against HCT116; and IC50 = 0.64 μM for compound 30 against A431 cell lines) with promising inhibitory properties against human DNA topoisomerase IIα. The safe profile of the anti-proliferative active agents against the RPE1 normal cell line may prove their selectivity towards carcinoma cells. Robust molecular models (2D-QSAR, 3D-pharmacophore) supported the SAR and validated the observed bio-properties.
Highlights
Curcumin 1 is one of the most famous dietary natural product dienones isolated from Curcuma longa and used in many Asian countries for its antiin ammatory and wound healing properties (Ayurvedic medicine)
Rational for insertion of carboxamide residue at N-1 of the targeted 3,5-bis(arylidene)-4-piperidones is stemmed from the fact that many clinically approved cancer drugs possess 1,3disubstituted urea function of which, Sorafenib 2, (Nexavar, Bayer Healthcare Pharmaceuticals Inc.) that was approved by the U
The piperidinyl methylene protons are observed as singlet signal at dH 1⁄4 4.88 in 1H-NMR spectrum
Summary
Dienone is an attractive chemical motif utilized by many researchers for designing promising biologically/ pharmacologically active agents.1–4 Curcumin 1 is one of the most famous dietary natural product dienones isolated from Curcuma longa and used in many Asian countries for its antiin ammatory and wound healing properties (Ayurvedic medicine).5–7 Curcumin analogues exhibit an extensive broad spectrum of biological properties such as antibacterial,8 antitubercular,9 anti-HIV,10 antioxidant,11 antitumor,7 and antiin ammatory12 activities and exhibit a potential therapeutic effect on Alzheimer's disease.4 Despite the safety pro le and broad spectrum biological properties of curcumin, it could not be approved as a therapeutic agent due to its high metabolic instability, low water/plasma solubility and poor systemicInterest in the piperidone ring system originate from the diverse biological properties showed by 1,3-diarylidene-4piperidones as antitumor,18–24 anti-mycobacterial,25 antimalarial26 and acetylcholinesterase inhibitor suggesting the usefulness for Alzheimer's disease treatment.27 The promising properties of 2,4-bis(arylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones against MCF7 (breast) and HepG2 (liver) carcinoma cell lines prompted the present study.28Rational for insertion of carboxamide residue at N-1 of the targeted 3,5-bis(arylidene)-4-piperidones is stemmed from the fact that many clinically approved cancer drugs possess 1,3disubstituted urea function of which, Sorafenib 2, (Nexavar, Bayer Healthcare Pharmaceuticals Inc.) that was approved by the U. From the results obtained (Table 1, ESI Fig. S96†), it has been noticed that the promising antiproliferative agents synthesized have IC50 towards RPE1 7–32, 4–11 and 5–14 folds relative to that of HCT116, MCF7 and A431 cell lines, respectively.
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