Design and synthesis of novel N,N′-glycoside derivatives of 3,3′-diindolylmethanes as potential antiproliferative agents

Abstract

A library of 34 compounds containing the DIM core have been synthesized and tested for their anticancer efficacy by measuring their cytotoxicity to cancer cell lines A549, HeLa and MCF-7. Some of the selected derivatives were N-glycosylated to increase their efficacy. Compound 7d, an N-glycosylated DIM derivative, was found to be effective at 1.3, 0.3 and 0.9 mmol concentrations against A549, HeLa and MCF-7, respectively. Immunochemistry studies revealed that it could induce apoptosis by upregulating a pro-apoptotic protein Par-4 and concomitantly diminishing the expression of prosurvival proteins Bcl-2 and GRP78. Flow cytometry studies showed that the compound arrested cells in the G1 phase of the cell cycle and significantly abrogated the motility of HeLa cells. Computer docking simulations of 7d with GRP78 suggested its involvement in two H-bonds with Asp78, two H-bonds with Arg290, one with Arg367, and one water mediated H-bond interaction. The interaction patterns also demonstrated that the presence of bromide in the vicinity (within 3.5 A) of Lys294 generates the possibility of a halogen bond, which may also contribute in providing some extra stability to the complex. Hence, compounds of this class will be useful for the design of new anticancer agents.

4′-Demethyl-deoxypodophyllotoxin glucoside isolated from Podophyllum hexandrum exhibits potential anticancer activities by altering Chk-2 signaling pathway in MCF-7 breast cancer cells

“…The inhibition constant (Ki) values for compound-5 was 3.2 lM in comparison to the reference compound PV1352, the Ki value of which was 2.8 lM against Chk2 conformer 2YIR. These computer simulated docking results supported the biological activity of compound-5 in modulating checkpoint kinase-2 [37,38].…”

Dual role of Par‐4 in abrogation of EMT and switching on Mesenchymal to Epithelial Transition (MET) in metastatic pancreatic cancer cells

“…Diindolylmethane (DIM) scaffolds are demonstrated for abrogation of EMT in diverse cancer models but yet to be explored for MET induction. The medicinal chemistry group of our laboratory synthesized and reported some novel derivatives of DIM with potential anticancer activities and by SAR analysis NGD16 (previously reported as compound 7d) was found to be the most active compound against a panel of cancer cell lines . Cell viability assay results unveiled that the IC 50 values of NGD16 in Panc‐1, MIA Paca‐2, HCT‐116, HT‐29, and BxPC‐3 were 2.5, 2.8, 3.7, 2.9, and 3.4 μM, respectively (Supplementary Table S1).…”

“…Streptomycin, Penicillin G, Trypsin‐EDTA, Phenylmethylsulfonyl fluoride (PMSF), Bradford reagent, Paraformaldehyde, Phosphate buffer saline, Protease inhibitor cocktail, Dimethylsulphoxide (DMSO), and Triton X‐100 used in the study were from Sigma Chemicals (St. Louis, MO). NGD16 was obtained from our Natural Plant Chemistry division, IIIM, Jammu and dissolved in DMSO . The final concentration of DMSO in the experiment never exceeded 0.2%.…”

“…Furthermore, DIM is also reported to induce the expression of Prostate apoptosis response 4 (Par-4). 43 Moreover, in one of our previous studies, we have established that NGD16 [1,1,-β-D-glucopyranosyl-3,3′-bis(5-bromoindolyl)octyl methane, 44 a potential N-glycosylated derivative of 3,3′,diindolylmethane, blocks angiogenesis by targeting the glucose regulated protein, 78 kDa (GRP78). 45 Given, angiogenesis is a crucial phenomenon that facilitates invasion and metastasis of tumor cells; rationally, in this study, for the first time, we have reported the MET-inducing ability of NGD16 exerted through Par4-mediated inhibition of EMT and invasion in metastatic pancreatic cancer cells.…”

“…2.2 | Chemicals, antibodies, and DNA construct St. Louis, MO). NGD16 was obtained from our Natural Plant Chemistry division, IIIM, Jammu and dissolved in DMSO 44. The final concentration of DMSO in the experiment never exceeded 0.2%.…”