Synthesis, evaluation of cytotoxic properties of promising curcumin analogues and investigation of possible molecular mechanisms

Abstract

Curcumin is a popular, plant-derived compound that has been extensively investigated for diverse range of biological activities. Anticancer activity against various types of cancers and high-safety profile associated with curcumin makes it very attractive. In this study, we report the synthesis and evaluation of pyrazole and click chemistry curcumin analogues for Head and Neck cancer. MTT assay against head and neck cancer cell lines CAL27 and UM-SCC-74A revealed the micromolar potency of the synthesized compounds. To determine the possible molecular mechanisms, effect of these analogues in the expression of pSTAT3, pFAK, pERK1/2 and pAKT was studied. Interestingly, compounds 2 and 5 significantly inhibited the pSTAT3 (Tyr 705) phosphorylation. As far as other compounds, they showed potent cytotoxicity against CAL27; however, these compounds did not show any activity on pSTAT3 phosphorylation at IC 50 concentration level. Molecular docking studies revealed the possible binding mode of pyrazole compound 2 in the SH2 domain of STAT3. K E Y W O R D Sclick chemistry curcumin analogue, curcumin, head and neck squamous cell carcinoma, pyrazole analogue Curcumin, a natural polyphenol which is used as a food colourant, and herbal medicine in Asia. Curcumin has received a lot of attention recently due to its high-safety profile and efficacy in treating various diseases.[1-3] Potential anticancer activities associated with curcumin make it a promising therapeutic agent. Apart from anticancer activity, it has shown antioxidant, anti-inflammatory, chemopreventive, chemotherapeutic, antimicrobial and antifungal activities. Curcumin (Figure 1) is being vigorously studied for its effect against breast cancer, prostate cancer, liver cancer, ovarian cancer and cervical cancer.[4] It demonstrated cytotoxic effects against cancer cell lines and cytoprotective effects on non-cancer cells. One of the important aspects of curcumin is its high-safety profile of up to 12 g per day oral administration.[5]Nevertheless, there are a number of challenges, low aqueous solubility, poor absorption and rapid metabolism that limits its therapeutic efficacy.[6] Curcumin can exist as a tautomeric mixture of keto and enol forms in solutions, and the enol form was found to be responsible for the rapid degradation of the curcumin. Chakraborti et al., [7] found that the stability of curcumin was improved when the central diketone moiety of the curcumin was replaced by isooxazole and pyrazole groups. Structural modifications of curcumin were proven to be a meaningful approach to discover analogues with enhanced properties. [8][9][10][11][12] Conjugates of curcumin with β-and γ-cyclodextrin, liposomal and loaded nanoparticles and nanoemulsion are some of the lipid-based colloidal system that has been employed to enhance water solubility and improving its bioavailability.[13] Recent work supports the

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application

“…[41] Curcumin analogs of benzyloxime and the isoxazole and pyrazole demonstrated outstanding amplification in the antitumor activity both in the parental and in the MDR MCF-7 cells. [42] Pyrazole and triazole curcumin analogs were synthesized and exhibited activity in micromolar against Head and Neck cancer. Cytotoxicity and cell death induction assays evidently indicted antitumor activity of curcumin analogs, which have substantial activity in both MCF-7 and in MCF-7R.…”

“…[63] Curcumin-pyrazole-Mannich derivatives have been recognized as potent inhibitors of Mycobacterium tuberculosis ( Table 6). [42] Pyrazole and triazole curcumin analogs were synthesized and exhibited activity in micromolar against Head and Neck cancer. Plausible molecular mechanisms, effects of these analogs in the expression of pSTAT3, pFAK, pERK1/2 and pAKT suggest inhibition of the pSTAT3 (Tyr 705) phosphorylation.…”

Curcuminoids: Implication for inflammation and oxidative stress in cardiovascular diseases

“…Currently, there are many different proposed strategies regarding synthetically improving its stability and activity; from side chain and diketone transformations to alkyl and alkenyl functionalization on C‐4, many have been reported (Gyuris et al, ) to ultimately create curcumin analogues such as C66 (Y. Wang et al, ), CA15 (J. Chen, Zhang, et al, ), A13 (Revalde et al, ), and NCB‐02 (Usharani, Mateen, Naidu, Raju, & Chandra, ). Conjugates of curcumin with β‐cyclodextrin and γ‐cyclodextrin, liposomal and loaded nanoparticles, and nanoemulsion are some of the lipid‐based colloidal systems that have been employed to enhance its release, water solubility, and bioavailability (Jordan et al, ). For example, a curcumin phosphatidylcholine complex has demonstrated an approximate 20‐fold increase in absorption in both rat and human studies following oral administration compared with the standard curcumin extract (Cuomo et al, ; Marczylo et al, ).…”

“…Wang et al, 2014), CA15 (J. Chen, , A13 (Revalde et al, 2017), and NCB-02 (Usharani, Mateen, Naidu, Raju, & Chandra, 2008). Conjugates of curcumin with β-cyclodextrin and γcyclodextrin, liposomal and loaded nanoparticles, and nanoemulsion are some of the lipid-based colloidal systems that have been employed to enhance its release, water solubility, and bioavailability (Jordan et al, 2017). For example, a curcumin phosphatidylcholine complex has demonstrated an approximate 20-fold increase in absorption in both rat and human studies following oral administration compared with the standard curcumin extract (Cuomo et al, 2011;Marczylo et al, 2007).…”

Curcuminoids versus Pyrazole‐Modified Analogues: Synthesis and Cytotoxicity against HepG2 Cancer Cell Line

“…Experimental and computational studies on curcumin structure demonstrated that the aromatic ring/substituents on it and β-diketone moieties are crucial for biological responses and kinetic stability. [1][2][3][4][5][6][7][8][9][10][11][12] Several synthetic curcumin analogues have been developed through chemical modifications on its pharmacophores such as pyrazole, [6,[13][14][15][16][17][18][19][20] 1,4-thiazepane, [7] monocarbonyl, [8] aza-aromatic, [9] N-alkyl β-enaminone curcuminoids. [10][11][12] to circumvent the limitations of curcumin.…”