Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (2a) and bicalutamide (3), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(N-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their N-methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b, which was comparable to hydroxyflutamide (2b). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans-amide bond, while the active N-methylated coumarinamides have a folded structure with a cis-amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.

Download Full-text

Molecular identification of Bifidobacterium sp. from local yoghurt and evaluation of growth inhibition activity against pathogenic bacteria

Bangladesh Journal of Scientific and Industrial Research ◽

10.3329/bjsir.v56i3.55962 ◽

2021 ◽

Vol 56 (3) ◽

pp. 147-154

Author(s):

AP Talukder ◽

MN Haque ◽

ML Mahmud ◽

MAE Ekram

Keyword(s):

Growth Inhibition ◽

Molecular Identification ◽

Inhibitory Activity ◽

Pathogenic Bacteria ◽

Inhibition Zone ◽

Antagonistic Activity ◽

E Coli ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Acinetobacter Sp

Yoghurt is a potential source of probiotic bacteria including Bifidobacterium sp. In this context, sour yoghurt sample was collected from local market in Rajshahi for molecular identification and characterization of Bifidobacterium sp. with promising antagonistic activity against pathogenic bacteria. Isolation was done on Luria broth agar media for molecular identification and revealed that isolated bacterium showed 90% similarity with Bifidobacterium sp. Antibiotic sensitivity test result revealed that isolated Bifidobacterium sp. was sensitive to erythromycin, kanamycin, gentamycin, tetracycline, ciprofloxacin, doxycycline out of eleven commercially used antibiotics. Moreover, antagonistic activity of Bifidobacterium sp. was evaluated in our present study against four pathogenic bacteriathrough disc diffusion method. Bifidobacterium sp. had relatively strong antagonistic effect (inhibition zone ≥15 mm) against Salmonella sp. with 16mm and 19mm zones of inhibition at doses of 150 and 200 μg/disc, respectively. Similarly, the isolate showed strong growth inhibitory activity against Acinetobacter sp. and E. coli with inhibition zone of 17 mm and 16 mm at dose of 200 μg/disc while moderate growth inhibitory activity was observed against Aeromonas sp. at applied four doses. Furthermore, present investigation showed that the isolated Bifidobacterium sp. had the utmost effect against Salmonella sp. and exhibited growth inhibition of understudy pathogens in such pattern Salmonella sp.>Acinetobacter sp.> E. coli> Aeromonas sp. Bangladesh J. Sci. Ind. Res.56(3), 147-154, 2021

Download Full-text

Isolation of tetramer stilbenoids from Shorea leprosula Miq., acetylcholinesterase inhibitory activity and molecular docking study

10.1055/s-0039-3399897 ◽

2019 ◽

Author(s):

AS Kamarozaman ◽

N Ahmat ◽

MSM Johari ◽

ZZ Hafiz ◽

MI Adenan ◽

...

Keyword(s):

Molecular Docking ◽

Inhibitory Activity ◽

Docking Study ◽

Molecular Docking Study ◽

Acetylcholinesterase Inhibitory Activity ◽

Shorea Leprosula

Download Full-text

Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

Pharmaceuticals ◽

10.3390/ph14010049 ◽

2021 ◽

Vol 14 (1) ◽

pp. 49

Author(s):

David Méndez-Luna ◽

Loreley Araceli Morelos-Garnica ◽

Juan Benjamín García-Vázquez ◽

Martiniano Bello ◽

Itzia Irene Padilla-Martínez ◽

...

Keyword(s):

Binding Site ◽

Cell Lines ◽

Cancer Cell ◽

Inhibitory Activity ◽

In Silico ◽

Cancer Cell Lines ◽

Pancreatic Cancer Cells ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

New Compounds

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.

Download Full-text

Indole-3-carbinol inhibits the proliferation of colorectal carcinoma LoVo cells through activation of the apoptotic signaling pathway

Human & Experimental Toxicology ◽

10.1177/09603271211021475 ◽

2021 ◽

pp. 096032712110214

Author(s):

JY Lee ◽

HM Lim ◽

CM Lee ◽

S-H Park ◽

MJ Nam

Keyword(s):

Colorectal Carcinoma ◽

Cancer Cells ◽

Inhibitory Activity ◽

Annexin V ◽

Fluorescein Isothiocyanate ◽

Cell Counting ◽

Terminal Deoxynucleotidyl Transferase ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Lovo Cells

Indole-3-carbinol (I3C) is a phytochemical that exhibits growth-inhibitory activity against various cancer cells. However, there are limited studies on the effects of I3C on colon cancer cells. In this study, the growth-inhibitory activity of I3C against the human colorectal carcinoma cell line (LoVo) was examined. The results of the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, colony formation, and cell counting assays revealed that I3C suppressed the proliferation of LoVo cells. Microscopy and wound-healing analyses revealed that I3C affected the morphology and inhibited the migration of LoVo cells, respectively. I3C induced apoptosis and DNA fragmentation as evidenced by the results of fluorescein isothiocyanate-conjugated annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling assay, respectively. Additionally, I3C arrested the cell cycle at the G0/G1 phase and enhanced the reactive oxygen species levels. Western blotting analysis revealed that treatment with I3C resulted in the activation of apoptotic proteins, such as poly(ADP-ribose) polymerase, caspase-3, caspase-7, caspase-9, Bax, Bim, and p53 in LoVo cells. These results indicate that I3C induces apoptosis in LoVo cells by upregulating p53, leading to the activation of Bax and caspases. Taken together, I3C exerts cytotoxic effects on LoVo cells by activating apoptosis.

Download Full-text