Synthesis and Cytotoxicity Evaluation of Novel Asymmetrical Mono-carbonyl Analogs of Curcumin (AMACs) against Vero, HeLa, and MCF7 Cell Lines

Abstract

A series of novel asymmetrical mono-carbonyl analogs of curcumin (AMACs) were synthesized and evaluated for cytotoxic activity using the brine shrimp lethality test (BSLT) and the methyl thiazolyl tetrazolium assay against Vero, HeLa, and MCF7 cell lines. The structures of the synthesized compounds were confirmed by Fourier transform infrared spectrophotometry (FTIR), 1H-nuclear magnetic resonance (NMR), 13C-NMR, and mass spectral data. The results of the cytotoxicity evaluation showed that the synthesized compounds exhibited moderate to very high toxic activity in BSLT, requiring a concentration of 13.06–714.49 µg/mL to kill half the population. Most of the compound exhibited cytotoxic activity against HeLa cell lines, comparable to the activity of cisplatin with a concentration of the synthesized compounds required to inhibit 50% of the growth of the cell lines (IC50) value of 40.65–95.55 µM, and most of the compounds tested against MCF7 cell lines exhibited moderate to very high cytotoxic activity (IC50 value 7.86–35.88 µM). However, the selectivity index of the compounds was low, less than 1–1.96. Among the synthesized compounds, compound 1b showed the highest cytotoxicity and selectivity against MCF7 cell lines. Compound 1b could be considered for further development to obtain more active and selective chemotherapeutic agents against breast cancer.

Ligand Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies of Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) to Discover Novel Estrogen Receptors Alpha (ERα) Inhibitor

“…None of the hits were Mannich base derivatives. The result was different from the result of in vitro evaluation against MCF-7 cell lines of the Mannich base of AMACs reported previously (active but nonselective) [8][9].…”

“…The asymmetrical hexahydro-2H-indazole curcumins (AIACs) were designed as the development of AMACs that refers to the modification of MACs into a symmetrical hexahydro-2H-indazole analog of curcumins (IACs) that provided good results for activity in several cancer cells including breast cancer cells [12]. The AMACs and derivatives exhibited cytotoxicity potential against HeLa, MCF-7, and WiDr cell lines [8][9], thus AIACs were also predicted to have cytotoxic activities as well. The structure of the designed AIACs (Table S1.c-f) had different substituents in one of the benzene rings (-H, -CH3, -F, -Cl, -OCH3, -dimethoxy) by considering their different characteristics of electronegativity, electronic charge, and induction effect of the substituents resulting in different geometric shapes for each analog compound.…”

“…The structures are shown in Table S1.a-g. A set of data of 34 ERα inhibitor compounds (Table S2.a-b) that consists of four native ligands of ER PDB and 30 other compounds with pIC50 values in the range of 4.40 to 9.86, were obtained from www.pubchem.com. The threedimensional (3D) Estrogen Homo sapiens receptor alpha (ERα) in the complex with E4D600 ligands (PDB code: 1SJ0) was obtained online from a database: NCBI, Research Collaboratory for Structural Bioinformatics Protein Data Bank http://www.pdb.org/pdb/home/ [9,16].…”

“…Diethylamine Mannich base substitution of the phenyl ring of MACs showed increased activity and selectivity of its anticancer properties [7]. Mannich base substitution of AMACs also showed cytotoxicity potential against HeLa, MCF-7, and WiDr cells [8][9]. The Mannich base acted as an important pharmacophore group in high-potential drugs [10].…”

Analysis of the essential oil from Lantana camara leaves and its cytotoxic potential against T-47D breast cancer cells

“…Hamidi et al (2014) explained that the level of toxicity of a compound is said to be non-toxic if the LC50 value is> 1000 µg / mL, low toxic if the LC50 is 500-1000 µg/mL, medium toxic if LC50 100-500 µg/mL and high toxic if LC50 0-100 µg/mL [29] . Prasetyaningrum et al (2018) also explained that if the toxic level of a compound with an IC50 value of <12 µg/mL or <30 µM) the compound is considered to have high cytotoxic activity (high toxic) [30] . Based on these data, it is known that the activity of the essential oil isolated from L. camara leaves is highly toxic, both tested against A. salina shrimp larvae (LC50 15.92 µg/mL) and T-47D breast cancer cells (IC50 10.67 µM).…”