Synthesis and biological evaluation of some novel 1,2,3-triazole hybrids of myrrhanone B isolated from Commiphora mukul gum resin: Identification of potent antiproliferative leads active against prostate cancer cells (PC-3)

• Published in: European journal of medicinal chemistry Vol. 188; p. 111974
• Main Authors: Madasu, Chandrashekhar, Karri, Shailaja, Sangaraju, Rajendra, Sistla, Ramakrishna, Uppuluri, Mallavadhani Venkata
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-02-2020
• Subjects: 1,2,3-Triazoles; Anti-diabetic; Anti-inflammatory; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Cell Line, Tumor; Commiphora - chemistry; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints - drug effects; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Humans; Molecular Structure; Myrrhanones B; Resins, Plant; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Triterpenes - chemical synthesis; Triterpenes - isolation & purification; Triterpenes - pharmacology; 1,2,3-Triazoles; Myrrhanones B; Anti-diabetic; Anticancer; Anti-inflammatory; Apoptosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111974

A series of 28 novel 1,2,3-triazole hybrids of myrrhanone B have been designed and synthesized by employing regioselective Cu catalyzed Huisgen 1,3-dipolar cycloaddition reaction in highly efficient manner. All the synthesized analogues were assessed for their antiproliferative potential against A549 (Lung), DU145 (Prostate), MDA-MB-231 (Breast), SiHa (Cervical), U87MG (Glioblastoma), PC-3 (Prostate), HT-29 (Colon), L132 (Normal lung) cell lines. Further, the synthesized hybrids have also been screened for anti-inflammatory activity (TNF-α and IL-1β) and α-glucosidase inhibitory activity. The biological results revealed that compound 11 (meta hydroxy phenyl 1,2,3–triazole) and compound 29 (deoxyuridine 1,2,3–triazole) found to be the most potent antiproliferative ones against PC-3 cell line. Compound 11 (IC50: 6.57 ± 0.62 μM) showed six folds more potent than parent compound 1 (IC50: 40.67 ± 2.2 μM) and displayed almost identical inhibitory activity with standard doxorubicin (IC50: 5.05 ± 0.25 μM), whereas compound 29 (IC50: 10.85 ± 0.90 μM) exhibited four folds more potent than parent myrrhanone B (1). In view of potent activity of compounds 11 and 29 they have been subjected to detailed flowcytometry analysis. Compound 29 treated cells significantly increased the SubG1 population of cells indicative of apoptosis compared to compound 11. Further, the results of anti-inflammatory studies indicated that compounds 3, 6, 9, 27, 28, 29 and 30 exhibited significant inhibitory activity against both TNF-α and IL-1β than the parent compound 1. Interestingly, compound 27 exhibited good activity towards inflammatory cytokines TNF-α (IC50: 7.83 ± 0.95 μM). Interestingly, α-glucosidase inhibitory assay results revealed that compounds 14 (IC50: 2.77 ± 0.59 μM) and 16 (IC50: 4.12 ± 0.77 μM) as the most potent ones. In fact, compound 14 exhibited highest activity and found to be several times more potent than the parent compound 1 as well as standard acarbose (IC50: 2124 ± 170 μM).
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•Myrrhanone B was isolated from the gum resin of Commiphora mukul.•Synthesized a series of 28 novel myrrhanone B based 1,2,3-triazole hybrids and screened for their antiproliferative, anti-inflammatory and anti-diabetic activities.•Compounds 11 and 29 exhibited potent antiproliferative activity against PC-3 cells and induced apoptosis in G0/G1 phase.•Compounds 28 and 29 showed good anti-inflammatory activity against TNF−α and IL-1β.•Compounds 14 and 16 exhibited potent α-glucosidase inhibitory activity.