Novel Curcumin Inspired Antineoplastic 1-Sulfonyl-4-Piperidones: Design, Synthesis and Molecular Modeling Studies

Abstract

Background: Curcumin is a well-known example of plant origin exhibiting promising diverse biological properties such as, anti-inflammatory and antitumor as well as poor pharmacokinetic/pharmacodynamic properties. This is why effective agents based on its chemical scaffold were explored. Methods: A set of 3,5-bis(ylidene)-1-(alkylsulfonyl)piperidin-4-ones were synthesized in excellent yield (80- 96%) through dehydrohalogenation reaction of 3,5-bis(ylidene)-4-piperidinones with the corresponding alkane sulfonyl chloride in the presence of triethylamine. Antiproliferative properties of the synthesized compounds (dienone/curcumin inspired analogues) were studied by the standard MTT technique. Results: Most of the synthesized compounds revealed antiproliferative properties against HCT116 (colon) and A431 (skin/squamous) cancer cell lines with IC50 values at sub-micromolar level. Compound 36 also exhibited potency against MCF7 (breast) and A549 (lung) cancer cell lines (IC50 = 2.23, 4.27µM, respectively) higher than that of the reference standards (IC50 = 3.15, 5.93µM for 5-fluorouracil and doxorubicin against MCF7 and A549 cell lines, respectively). Cytotoxic properties of the synthesized compounds against non-cancer RPE1 cell line supported the safety profile of the effective agents against normal cells. Molecular modeling (3Dpharmacophore and 2D-QSAR) studies validated the observed bio-properties and explained the parameters governing activity. Inhibitory properties of compounds 27 and 29 (representative examples of the promising antiproliferative agents synthesized) supported their mode of action against topoisomerase IIα Conclusion: The synthesized scaffold is a promising antitumor agent (with special selectivity against colon and skin/squamous cancer cell lines) so, it can be considered for further investigation and development of highly effective hits/leads based on the computational models obtained.

Polychemotherapy with Curcumin and Doxorubicin via Biological Nanoplatforms: Enhancing Antitumor Activity

“…Smart nanomaterials (e.g., pH-sensitive and redox-sensitive nanoparticles) can be applied for targeted delivery of curcumin and DOX, to release their cargo in response to the tumor microenvironment. Besides, the surface of nanoparticles can be modified by receptors and ligands (such as hyaluronic acid and RGD) to promote accumulation in cancer cells (Figure 6) [222][223][224][225][226][227][228][229][230][231][232][233][234]. In Table 3, different nanocarriers applied for codelivery of curcumin and DOX are described.…”

Synthesis and molecular modeling studies of cholinesterase inhibitor dispiro[indoline-3,2′-pyrrolidine-3′,3′′-pyrrolidines]

“…Antiproliferative properties of the synthesized agents 8a-l were considered against RPE1 (human immortalized retinal pigment epithelial cell line) normal cell line utilizing the standard MTT (tetrazolium salt) technique. 37 The adopted technique is useful for exploring the cytotoxicity properties of the synthesized agents. From the obtained results (ESI Fig.…”

“…The synthesized agents 8a-l were screened against RPE1 (human immortalized retinal pigment epithelial cell line) normal cell line to investigate their cytotoxicity by the standard mitochondrial dependent reduction of yellow MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to purple formazan technique. 37 Cells were suspended in DMEM in addition to 1% antibiotic-antimycotic mixture (10 000 mg mL À1 potassium penicillin, 10 000 mg mL À1 streptomycin sulfate and 25 mg mL À1 amphotericin B), 10% fetal bovine serum and 1% L-glutamine at 37 C, under 5% CO 2 and 95% humidity. Cells were seeded at concentration of 30 000 cells per well in fresh complete growth medium in 96well tissue culture microtiter plates for 24 h. Media was aspirated, fresh complete medium was added and cells were incubated with different concentrations of the tested compound to give a nal concentration of (100, 50, 25 and 12.5 mM).…”

3-Alkenyl-2-oxindoles: Synthesis, antiproliferative and antiviral properties against SARS-CoV-2

“…In our pursuit to develop novel antitumor agents [11] , [12] , [13] , the present study describes the synthesis of 3-alkenyl-2-oxindoles conjugated with sulfonamide function. This fragment is an important component in many clinically approved antitumor drugs {e.g.…”