Nano-Zirconium Dioxide Catalyzed Multicomponent Synthesis of Bioactive Pyranopyrazoles That Target Cyclin Dependent Kinase 1 in Human Breast Cancer Cells

Abstract

Small molecules are being used to inhibit cyclin dependent kinase (CDK) enzymes in cancer treatment. There is evidence that CDK is a drug-target for cancer therapy across many tumor types because it catalyzes the transfer of the terminal phosphate of ATP to a protein that acts as a substrate. Herein, the identification of pyranopyrazoles that were CDK inhibitors was attempted, whose synthesis was catalyzed by nano-zirconium dioxide via multicomponent reaction. Additionally, we performed an in-situ analysis of the intermediates of multicomponent reactions, for the first-time, which revealed that nano-zirconium dioxide stimulated the reaction, as estimated by Gibbs free energy calculations of spontaneity. Functionally, the novel pyranopyrazoles were tested for a loss of cell viability using human breast cancer cells (MCF-7). It was observed that compounds 5b and 5f effectively produced loss of viability of MCF-7 cells with IC50 values of 17.83 and 23.79 µM, respectively. In vitro and in silico mode-of-action studies showed that pyranopyrazoles target CDK1 in human breast cancer cells, with lead compounds 5b and 5f having potent IC50 values of 960 nM and 7.16 μM, respectively. Hence, the newly synthesized bioactive pyranopyrazoles could serve as better structures to develop CDK1 inhibitors against human breast cancer cells.

Electrochemical Synthesis of Versatile Pyrimidine and Oxadiazoles Tethered Triazoles as Inhibitors of VEGFR-2 in Human Breast Cancer Cells

“…Further, the propargylation of 6-methyl-2-thiouracil (9) was achieved in refluxing ethanol:water under basic conditions. 4-hydroxy-coumarins (3a/11), upon refluxing with bromochloropropane in DMF, yields compound (12). After purification, this compound was used for the next step by treating it with propargylated 6-methyl-2-thiouracil (10) in refluxing acetone, yielding compound (13).…”

“…Heterocycles have been widely studied and integrated into medicinal chemistry due to their diverse biological activities, including targeting specific cellular pathways, DNA binding, alkylation, and apoptosis induction [4,5]. Presently, extensive research is focusing on various natural and synthetic heterocyclic compounds, such as pyrimidines [6][7][8], coumarins [9,10], pyrazoles [11][12][13], triazoles [14][15][16], oxadiazoles [17][18][19], and piperazines [20,21], among others, which have displayed promising biological properties.…”

“…Zebrafish studies demonstrate the more substantial anti-angiogenic potential of indole-2-one substituted 1,2,3-triazole (11) than that of sunitinib. Certain pyrimidine and pyridine-based motifs (12,13,14) In recent years, electrochemistry has garnered increasing attention as a prominent method in synthetic chemistry, particularly within the context of green synthesis [62][63][64]. Electrochemical synthesis stands as a chemical procedure entailing an intricate interplay with electron transfer occurring at an electrode interface.…”

Recent Synthesis of Mono‐ & Bis‐Pyranopyrazole Derivatives

“…Sajjadi et al (2023), for instance, reported on the synthesis of dihydropyrano[2,3c]pyrazoles via Knoevenagel-Michael multiple reactions by using green catalyst Fe 3 O 4 @gC 3 N 4 for the reaction of aldehydes, phenylhydrazine, ethyl acetoacetate and malononitrile under 1 h reflux to achieve 97 % yield of product (Route 1). [51] This reaction has also been reported by using numerous catalysts such as 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate ([DBU][Ac], [59] HMS/PrÀ Rh-Zr, [60] H 3 PO 4 /Al 2 O 3 , P 2 O 5 /SiO 2 , starch sulfuric acid, cellulose sulfuric acid, [61] thiourea dioxide (TUD), [62] PVCÀ EDAÀ CeIII, [63] citrus limon (lemon juice), [64] agave leaf ash extract, [65] piperidine, [66] sodium lactate, [67] NiWO 4 , [68] PBCMOamine, [69] CaO nanoparticles, [70] Fe 3 O 4 @chitosan-tannic acid bionanocomposite, [71] FSiPSS nano-catalyst, [72] nano ZrO 2 , [73] lactic acid : urea : NH 4 Cl, [74] H 4 [SiW 12 O 40 ], [75] NiFe 2 O 4 @SiO 2 À H 3 PW 12 O 40 (NFSÀ PWA), [76] Fe 3 O 4 @SiO 2 @CoSB, [77] PAN@melamine/Fe 3 O 4 nanocomposite, [78] isonicotinic acid, [79] nano-[Fe-PSMP]Cl 2 , [80] Fe 3 O 4 /MIP-202-H 4 WO 5 , [81] Zn(L-proline) 2 , [82] baker's yeast, [83] solar radiation, [84] Cu-DABP@Fe 3 O 4 /MCM-41, [85] Fe 3 O 4 @NFC@Co(II), [86] PdO/Al-SBA-15, [87] (MnCoFe 2 O 4 @Niacin-SO 3 H) + Cl À , [88] Zn-CA-MOFs [89] and Na 2 CaP 2 O 7 . [90] In 2022, Nguyen and coworkers reported different routes to the synthesis of pyrano[2,3-c]pyrazole derivatives, which involved a four-component reaction of benzyl alcohols, phenylhydrazine, ethyl acetoacetate and malononitrile with the aid of sulfonated amorphous carbon and eosin Y as c...…”

Synthesis of novel triazoles as anticancer agents targeting pJNK in human breast cancer cells

“…28,29 In our previous report, we reported the synthesis of triazolyloxadiazole I, as an anticancer agent. 30 To explore the structural diversity of the molecule we synthesized triazoles by forming a 1,2,4-triazole ring instead of a 1,3,4-oxadiazole ring and evaluated its anticancer activity targeting JNK in MCF-7 cells.…”