An efficient diversity-oriented synthetic approach to annulated 9H-benzobpyrrolo1,2-g1,2,3triazolo1,5-d1,4diazepines has been developed using a Sc(OTf)3-catalyzed two-component tandem C-2 ...functionalization-intramolecular azide-alkyne 1,3-dipolar cycloaddition reaction. The reaction shows high substrate tolerance and provides a library of fused heterocycles that may lead to novel biologically active compounds or drug lead molecules.
The present study was undertaken to explore the functional involvement of Hh signaling and its regulatory mechanism in endometrial hyperplasia. Differential expression of Hh signaling molecules i.e., ...Ihh, Shh, Gli1 or Gsk3β was observed in endometrial hyperplasial (EH) cells as compared to normal endometrial cells. Estradiol induced the expression of Hh signaling molecules and attenuated the expression of Gsk3β whereas anti-estrogen (K1) or progestin (MPA) suppressed these effects in EH cells. Cyclopamine treatment or Gli1 siRNA knockdown suppressed the growth of EH cells and reduced the expression of proliferative markers. Estradiol also induced the nuclear translocation of Gli1 which was suppressed by both MPA and K1 in EH cells. While exploring non-canonical mechanism, LY-294002 (Gsk3β activator) caused a decrease in Gli1 expression indicating the involvement of Gsk3β in Gli1 regulation. Further, Gsk3β silencing promoted the expression and nuclear translocation of Gli1 demonstrating that Gsk3β serves as a negative kinase regulator of Gli1 in EH cells. Similar attenuation of Hh signaling molecules was observed in rats with uterine hyperplasia undergoing anti-estrogen treatment. The study suggested that Hh/Gli1 cascade (canonical pathway) as well as Gsk3β-Gli1 crosstalk (non-canonical pathway) play crucial role in estrogen-dependent cell proliferation in endometrial hyperplasia.
A rapid and versatile, transition metal free, green methodology for the synthesis of 2,5-disubstituted-1H-imidazoles, using gem-dibromo vinylarenes and amidines is described. The disclosed strategy ...utilizes a combination of the easily available and nontoxic, naturally occurring mild base, NaHCO
3
and the ionic liquid, 1-butyl-3-methyl imidazolium tetrafluoroborate bmimBF
4
, for promoting the successive aminations through intermolecular C(sp
2
)-N and intramolecular C(sp
2
)-N bonds formation to furnish diverse disubstituted imidazole derivatives.
The development of versatile new routes to bridgehead nitrogen-bearing polycyclic aromatic systems having privileged scaffolds is a synthetic challenge for organic chemists. An efficient synthesis of ...benzo4,5imidazo1,2-aquinazoline derivatives bearing bridgehead nitrogen by the reaction of benzodimidazol-2-amines, aldehydes, and ortho-silyl aryltriflate via 1,4-dipolar cycloaddition is reported under the optimized reaction conditions. The methodology provides easy access to fused benzimidazolo-quinazolines by sequential C-N and C-C bond formation through a one-pot reaction.
A new and highly efficient visible-light-promoted catalyst free (VLCF) strategy for neat and clean synthesis of spiro indolo-quinazolinone-pyrrolo3,4-apyrrolizine hybrids (6a-d) has been introduced. ...We have performed visible-light triggered 1,3-Dipolar cycloaddition reaction of maleimide (5a-d) with azomethine ylide generated in situ derived from tryptanthrin (3) and L-proline (4) to obtain desired products (6a-d) in good to excellent yield. Authentication and characterization of product was done using various spectroscopic techniques such as IR,
1
H NMR,
13
C NMR, Mass spectrometry and single crystal XRD analysis. To explain the reaction spontaneity, product stability, reactivity as well as possible mode of the interaction a quantum chemical investigation was performed and depicted through DFT studies. The synthesized compound 6a was also evaluated for anti-proliferative activity against a panel of five cancer cell lines (MCF-7, MDA-MB-231, HeLa, PC-3 and Ishikawa) and normal human embryonic kidney (HEK-293) cell line by using MTT assay. Compound 6a showed very good in vitro anti-proliferative activity (IC
50
= 6.58-17.98 μM) against four cancer cell lines and no cytotoxicity against normal HEK-293. In order to evaluate the anticancer potential of compounds 6a-d, molecular docking was performed against wild type and mutant EGFR. The results suggest that all the compounds occupied the active site of both enzymes, with a strong binding energy (−10.2 to −11.5 kcal/mol). These results have been confirmed by molecular dynamics simulation by evaluating root mean square deviation (RMSD) and root mean square fluctuation (RMSF), along with principal component analysis (PCA).
Communicated by Ramaswamy H. Sarma
Existing cancer therapies are often associated with drug resistance and toxicity, which results in poor prognosis and recurrence of cancer. This necessitates the identification and development of ...novel therapeutics against existing as well as novel cellular targets. In this study, a novel class of Benzocoumarin-Stilbene hybrid molecules were synthesized and evaluated for their antiproliferative activity against various cancer cell lines followed by in vivo antitumor activity in a mouse model of cancer. The most promising molecule among the series, i.e. compound (E)-4-(3,5-dimethoxystyryl)-2H-benzohchromen-2-one (19) showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. The mechanistic studies of compound 19 by various biochemical, cell biology and biophysical approaches suggest that the compound binds to and inhibits the human DNA ligase I enzyme activity that might be the cause for significant reduction in tumor growth and may constitute a promising next-generation therapy against breast cancers.
Polo-like kinase-1 (PLK-1) is an essential mitotic serine/threonine (Ser/Thr) kinase that belongs to the Polo-like kinase (PLK) family and is overexpressed in non-small cell lung cancer (NSCLC) via ...promotion of cell division. Therefore, PLK-1 may act as a promising target for the therapeutic cure of various cancers. Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. To the best of our knowledge, no anticancer agent has been reported from marine algae or microorganisms to date. Thus, the aim of the present study is a high-throughput virtual screening of phlorotannins, obtained from edible brown algae, using molecular docking and molecular dynamic simulation analysis. Among these, Pentafuhalol-B (PtB) showed the lowest binding energy (best of triplicate runs) against the target protein PLK-1 as compared to the reference drug volasertib. Further, in MD simulation (best of triplicate runs), the PtB-PLK-1 complex displayed stability in an implicit water system through the formation of strong molecular interactions. Additionally, MMGBSA calculation (best of triplicate runs) was also performed to validate the PtB-PLK-1 complex binding affinities and stability. Moreover, the chemical reactivity of PtB towards the PLK-1 target was also optimised using density functional theory (DFT) calculations, which exhibited a lower HOMO-LUMO energy gap. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer.
Herein, we report an efficient and eco-friendly, ultrasound assisted synthetic strategy for the construction of diversified pyrrolobenzodiazepine-triazole hybrids, which are potentially ...pharmaceutically important scaffolds, via a domino reaction involving intermolecular electrophilic substitution followed by intramolecular Huisgen 1,3-dipolar azide-alkyne cycloaddition. The USP of the reported protocol is the use of benign and inexpensive, recyclable molecular iodine-ionic liquid synergistic catalytic system cum reaction media for achieving the synthesis. The other salient features of this method are the use of mild reaction conditions, high yield and atom economy, operational simplicity, broad substrate scope and easy workup and purification. All the synthesized compounds were evaluated for
anti-proliferative activity against various cancer cell lines. From among the synthesized title compounds, 9,9-dimethyl-8-phenyl-9H-benzo bpyrrolo 1,2-d1,2,3triazolo5,1-g1,4diazepine (7) was found most to be the most active compound exhibiting IC
value of 6.60, 5.45, 7.85, 11.21, 12.24, 10.12, and 11.32 µM against MCF-7, MDA-MB-231, HeLa, SKOV-3, A549, HCT-116 and DLD-1 cell lines, respectively. Further the compounds were found to be non-toxic against normal human embryonic kidney (HEK-293) cell line.
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This review explores the recent advancements in the design and synthesis of pseudo-natural products (pseudo-NPs) by employing innovative principles and strategies, heralding a ...transformative era in chemistry and biology. Pseudo-NPs, produced through in silico fragmentation and the de novo recombination of natural product fragments, reveal compounds endowed with distinct biological activities. Their advantage lies in transcending natural product structures, fostering diverse possibilities. Research in this area over the past decade has yielded unconventional combinations of natural product fragments, leading to the identification of novel compounds possessing unique scaffolds and biological significance, thereby contributing to the discovery of new therapeutics. The pseudo-NPs exert potent biological effects through various signaling pathways. In chemical biology and medicinal chemistry, designing pseudo-NPs is an important strategy, harnessing molecular hybridization and bioinspired synthesis to generate diverse compounds with remarkable biological activities, underscoring their immense potential in drug discovery and development.
Background
Antimicrobial peptides are very primitive innate defense molecules of almost all organisms, from microbes to mammalians and vascular seed-bearing plants. Antimicrobial peptides of plants ...categorized into cysteine-rich peptides (CRPs) and others and most of the antimicrobial peptides belong to CRPs group. These peptides reported showing the great extent of protecting property against bacteria, fungi, viruses, insect, nematode, and another kind of microbes. To develop a resistant plant against pathogenic fungi, there have been several studies executed to understand the efficiency of transgenicity of these antimicrobial peptides.
Main text
Apart from the intrinsic property of the higher organism for identifying and activating microbial attack defense device, it also involves innate defense mechanism and molecules. In the current review article, apart from the structural and functional characterization of peptides defensin and thionin, we have attempted to provide a succinct overview of the transgenic development of these defense peptides, that are expressed in a constitutive and or over-expressive manner when biotic and abiotic stress inflicted. Transgenic of different peptides show different competence in plants. Most of the transgenic studies made for defensin and thionin revealed the effective transgenic capacity of these peptides.
Conclusion
There have been several studies reported successful development of transgenic plants based on peptides defensin and thionin and observed diverse level of resistance-conferring potency in different plants against phytopathogenic fungi. But due to long regulatory process, there has not been marketed any antimicrobial peptides based transgenic plants yet. However, success report state that possibly in near future transgenic plants of AMPs would be released with devoid of harmful effect, with good efficiency, reproducibility, stability, and least production cost.
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