1H-1,2,3-Triazole tethered
imidazole–isatin and imidazole–isatin–thiosemicarbazone
conjugates were synthesized and evaluated against MCF-7 and MDA-MB-231
cell lines. Antiproliferative activities of the synthesized conjugates
revealed an optimum combination of longer alkyl chain length as spacer
and a halogen-substituent on the isatin ring as a pre-requisite for
good activity. The compound 6g with an optimum combination
of chloro-substituent at C-5 position of isatin ring and a butyl chain
length proved to be most active and noncytotoxic with IC50s of 54.25 and 26.12 μM against MCF-7 and MDA-MB-231 cell lines,
respectively.
A library of 1H-1,2,3-triazole-tethered ospemifene–isatin and ospemifene–spiroisatin conjugates have been synthesized and evaluated for their anti-proliferative activities against MCF-7 and MDA-MB-231 cell lines.
A series of tetrahydro-β-carboline–isatin conjugates was prepared and assayed for anti-proliferative activities on Estrogen Responsive ER(+) and non-responsive ER(−ve) cell-lines.
a b s t r a c tDespite new agent development and short-term benefits in patients with colorectal cancer (CRC), metastatic CRC cure rates have not improved due to high rates of 5-fluorouracil (5-FU)/leucovorin/ oxaliplatin (FOLFOX)-resistance and a clinical therapeutic plateau. At the same time, this treatment regime leads to significant toxicity, cost, and patient inconvenience. Drug-resistance is linked to CRC stem cells, which are associated with the epidermal-to-mesenchymal transition (EMT) pathway. Thus, to optimally treat CRC, a therapy that can target the cell survival and EMT pathways in both CRC bulk and stem cell populations is critical. We recently identified a novel small molecule NSC30049 (7a) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC bulk, FOLFOXresistant, and CRC stem cells both in vitro and in vivo models. In the present study, we report the synthesis and anti-CRC evaluation of several stable and effective 7a analogs. ASR352 (7b) was identified as one of the equipotent 7a analogs that inhibited the growth of CRC bulk cells, sensitized FOLFOX-resistant cells, and reduced the sphere formation capacity of CRC stem cells. It appears that the complex mechanism of cytotoxicity for 7b includes abrogation of 5-FU-induced the S phase, reduction of the phosphorylation of Chk1 at S317P, S345P and S296P, increased gH2AX staining, activation of caspase 3/PARP1 cleavage, and enhancement of Bax/Bcl2 ratio. Further 7b-mediated reduced phosphorylation of Chk1 was an indirect effect, since it did not inhibit Chk1 activity in an in vitro kinase assay. Our findings suggest that 7b as a single agent, or in combination with 5-FU can be developed as a therapeutic agent in CRC bulk, FOLFOX-resistant, and CRC stem cell populations for unmanageable metastatic CRC conditions.
The manuscript describes a straightforward and atom-efficient method for the synthesis of α-alkylidene-β-lactams using sorbyl tosylate and imines/1-azadienes at high temperature (80°C). The Density functional theory calculations have shown the prevalence of the first order kinetics in these [2 + 2] cyclo-additions to produce mixture of 3-butadienyl-azetidin-2ones and 3-but-2-enylidene-azetidin-2-ones in good yields. The 3but-2-enylidene-azetidin-2-ones have also shown antimicrobial activity against the E. coli, S. aureus, P. aeruginosa, B. cereus and B. subtilis.
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