Agents which can recognize and bind specific sequences of DNA offer selective therapy through the modulation of specific transcription factors or genes. Recently, there has been renewed interest in ...the field of anticancer minor groove binders. This may be attributed to the fact that many compounds of this class have demonstrated significant antitumor activity against a wide variety of cancers in recent clinical trials. This review will discuss the recent efforts to overcome the drawbacks of existing minor groove binding anticancer agents through rational drug design based on scaffolds with known antitumor activity.
Microwave-assisted (MWA) multicomponent reactions (MCRs) have successfully emerged as one of the useful tools in the synthesis of biologically relevant heterocycles. These reactions are strategically ...employed for the generation of a variety of heterocycles along with multiple point diversifications. Over the last few decades classical MCRs such as Ugi, Biginelli, etc. have witnessed enhanced yield and efficiency with microwave assistance. The highlights of MWA-MCRs are high yields, reduced reaction time, selectivity, atom economy and simpler purification techniques, such an approach can accelerate the drug discovery process. The present review focuses on the recent advances in MWA-MCRs and their mechanistic insights over the past decade and shed light on its advantage over the conventional approach.
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•A new series of 1,2,4-triazole-urea/thiourea conjugates were synthesized.•Compound 5t induced apoptosis and cell cycle arrest in G0/G1 phase in MCF-7 cell line.•Compound 5t inhibited ...colony formation in MCF-7 cell line.•Compound 5t was almost 2 times more selective on MCF-7 cells compared to L-132 cells.
A new series of 1,2,4-triazole-linked urea and thiourea conjugates have been synthesized and evaluated for their in vitro cytotoxicity against selected human cancer cell lines namely, breast (MCF-7, MDA-MB-231), lung (A549) prostate (DU145) and one mouse melanoma (B16-F10) cell line and compared with reference drug. The compound 5t showed significant cytotoxicity on MCF-7 breast cancer cell line with a IC50 value of 7.22 ± 0.47 µM among all the tested compounds. Notably, induction of apoptosis by compound 5t on MCF-7 cells was evaluated using different staining techniques such as acridine orange/ethidium bromide (AO/EB), annexin V-FITC/PI, and DAPI. Further, clonogenic assay indicates the inhibition of colony formation on MCF-7 cells by compound 5t. Moreover, the flow-cytometric analysis also revealed that compound 5t caused the arrest of cells at G0/G1 phase of cell cycle. In addition, the compounds when tested on normal human cells (L-132) were found to be safer with low cytotoxicity profile.
The efficacy of successful cancer therapies is frequently hindered by the development of drug resistance in the tumor. The term 'drug resistance' is used to illustrate the decreased effectiveness of ...a drug in curing a disease or alleviating the symptoms of the patient. This phenomenon helps tumors to survive the damage caused by a specific drug or group of drugs. In this context, studying the mechanisms of drug resistance and applying this information to design customized treatment regimens can improve therapeutic efficacy as well as the curative outcome. Over the years, numerous Multidrug Resistance (MDR) mechanisms have been recognized and tremendous effort has been put into developing agents to address them. The integration of data emerging from the elucidation of molecular and biochemical pathways and specific tumor-associated factors has shown tremendous promise within the oncology community for improving patient outcomes. In this review, we provide an overview of the utility of these molecular and biochemical signaling processes as well as tumor-associated factors associated with MDR, for the rational selection of cancer treatment strategies.
A novel strategy towards the synthesis of 1,4-disubstituted 1,2,3-triazoles
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C-N and N-N bond formation has been demonstrated under transition metal-free and azide-free conditions. These ...1,2,3-triazoles were obtained in a regioselective manner from commercially available anilines, aryl alkenes/aryl alkynes and
N
-tosylhydrazines using I
2
under O
2
atmosphere. Broad substrate scope, milder reaction conditions, good to moderate yields and clean protocol are the notable features of the method. Moreover, this protocol is amenable for the generation of a library of medicinally important key building blocks.
A novel strategy towards the synthesis of 1,4-disubstituted 1,2,3-triazoles
via
C-N and N-N bond formation has been demonstrated under transition metal-free and azide-free conditions.
To synthesize a series of phenanthrene-thiazolidinedione hybrids and explore their cytotoxic potential against human cancer cell lines of A-549 (lung cancer), HCT-116 and HT-29 (colon cancer), MDA ...MB-231 (triple-negative breast cancer), BT-474 (breast cancer) and (mouse melanoma) B16F10 cells.
A new series of phenanthrene-thiazolidinedione hybrids was synthesized via Knoevenagel condensation of phenanthrene-9-carbaldehyde and N-alkylated thiazolidinediones. The cytotoxicity (IC
) of the synthesized compounds was determined by MTT assay. Apoptotic assays like (AO/EB) and DAPI staining, cell cycle analysis, JC-1 staining and Annexin V binding assay studies were performed for the most active compound (Z)- 3-(4-bromobenzyl)-5-((2,3,6,7-tetramethoxyphenanthren-9-yl)methylene)thiazolidine-2,4-dione (17b). Molecular docking, dynamics and evaluation of pharmacokinetic (ADME/T) properties were also carried out by using Schrödinger.
From the series of tested compounds, 17b unveiled promising cytotoxic action with an IC
value of 0.985±0.02μM on HCT-116 human colon cancer cells. The treatment of HCT-116 cells with 17b demonstrated distinctive apoptotic morphology like shrinkage of cells, horseshoe-shaped nuclei formation and chromatin condensation. The flow-cytometry analysis revealed the G0/G1 phase cell cycle arrest in a dosedependent fashion. The AO/EB, DAPI, DCFDA, Annexin-V and JC-1 staining studies were performed in order to determine the effect of the compound on cell viability. Computational studies were performed by using Schrödinger to determine the stability of the ligand with the DNA.
The current study provides an insight into developing a series of phenanthrene thiazolidinedione derivatives as potential DNA interactive agents which might aid in colon cancer therapy.
A mild and metal-free one-pot synthetic strategy has been developed for the construction of substituted pyrroles by employing aza-Wittig reaction from a unique and unexplored combination of chromones ...and phenacyl azides. This method does not compromise the diverse substitutions on both the phenacyl azides and chromones. The merits of this method are wide substrate scope, easy functionalization, short reaction time, operationally simple, and higher yields. Moreover, this method is amenable for the generation of a library of key pyrrole building blocks.
A mild and metal-free one-pot synthetic strategy has been developed for the construction of substituted pyrroles by employing aza-Wittig reaction from a unique and unexplored combination of chromones and phenacyl azides.
A series of β‐carboline hybrids bearing a substituted phenyl and a chalcone/(N‐acetyl)‐pyrazole moiety at the C1 and C3 positions, respectively, was designed, synthesized, and evaluated for ...anticancer activity. These new hybrid molecules showed significant cytotoxic activity, with IC50 values ranging from <2.0 μM to 80 μM, and the structure–activity relationships (SAR) associated with substitutions at positions 1 and 3 of these hybrids was clearly addressed. Further, induction of apoptosis was confirmed by Annexin V‐FITC, Hoechst staining, and DNA fragmentation analysis. In addition, DNA photocleavage studies proved that two of the hybrids, (E)‐1‐(furan‐2‐yl)‐3‐(1‐(4‐(trifluoromethyl)phenyl)‐9H‐pyrido3,4‐bindol‐3‐yl)prop‐2‐en‐1‐one (7 d) and 1‐(3‐(furan‐2‐yl)‐5‐(1‐(4‐(trifluoromethyl)phenyl)‐9H‐pyrido3,4‐bindol‐3‐yl)‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)ethanone (8 d) could effectively cleave pBR322 plasmid DNA upon irradiation with UV light. Active hybrid 8 d inhibited DNA topoisomerase I activity efficiently and preserved DNA in the supercoiled form. To further corroborate the biological activities, as well as to understand the nature of the interaction of these hybrids with DNA, spectroscopic studies were also performed. Unlike simple β‐carboline alkaloids, the binding mode of these new hybrid molecules with DNA was not similar, and both biophysical as well as molecular docking studies speculated a combilexin‐type of interaction with DNA. Further, an in silico study of these β‐carboline hybrids revealed their drug‐like properties.
Hybridization Station: A series of new β‐carboline hybrids were designed, synthesized, and evaluated for their anticancer activity. Induction of apoptosis was confirmed by Annexin V‐FITC, Hoechst staining, and DNA fragmentation analysis. The interaction of these hybrids with DNA, as well as with topoisomerase I, was also studied using docking experiments.
The phenanthrene nucleus is extensively found in diverse natural products and its versatility is not just limited to pharmaceutically beneficial molecules but has proved efficient in the development ...and synthesis of dyes, plastics, pesticides and explosives. Such a relevant nucleus has attracted researchers to probe into the construction of phenanthrene nucleus. The past two decades have witnessed continuous efforts in this direction with the exploration of various synthetic strategies enabling access to the privileged core. The review focuses on bringing the advances made in 20 years in these synthetic protocols and the mechanism involved in the generation of phenanthrene and its derivatives under one roof. In addition, it also provides a comparative study of the diverse approaches and vivid reactions employed for phenanthrene synthesis providing a better understanding and creating newer ideas towards the development of new chemical entities (NCEs).
This review focuses on the efficient approaches and mechanistic aspects employed in the construction of the phenanthrene nucleus which offers not just therapeutic application but are also relevant with their electrochemical and photochemical properties.
A facile 3 + 2cycloaddition/oxidation/aromatization cascade reaction for the synthesis of pyrrolo2,1- a isoquinolines and indolizino8,7- b indoles has been developed. This tandem approach was ...accomplished by employing tert -butyl hydroperoxide (TBHP) as the environmentally benign stoichiometric oxidant, with the catalysis of non-toxic tetrabutylammonium iodide (TBAI) and isopropanol as the green solvent. Gratifyingly, this protocol is highly versatile, as the construction of polycyclics could be tailored by readily available dipolarophiles. Only a catalytic amount of TBAI was required, as the hypervalent electrophilic iodine species (IOH) can be recovered in situ by oxidation with TBHP. Furthermore, for the first time, the mechanistic aspects and the putative intermediates associated with this cascade have been intercepted and characterized by online monitoring of the reaction by using ESI-MS/MS.
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