Ring fusion strategy for synthesis and lead optimization of sulfur-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivatives as promising scaffold of antitumor agents

Mokgautsi

et al. 2021

Cells

Self Cite

Tumor recurrence from cancer stem cells (CSCs) and metastasis often occur post-treatment in colorectal cancer (CRC), leading to chemoresistance and resistance to targeted therapy. MYC is a transcription factor in the nuclei that modulates cell growth and development, and regulates immune response in an antitumor direction by mediating programmed death ligand 1 (PD-L1) and promoting CRC tumor recurrence after adjuvant chemotherapy. However, the molecular mechanism through which c-MYC maintains stemness and confers treatment resistance still remains elusive in CRC. In addition, recent reports demonstrated that CRC solid colon tumors expresses C-X-C motif chemokine ligand 8 (CXCL8). Expression of CXCL8 in CRC was reported to activate the expression of PD-L1 immune checkpoint through c-MYC, this ultimately induces chemoresistance in CRC. Accumulating studies have also demonstrated increased expression of CXCL8, matrix metalloproteinase 7 (MMP7), tissue inhibitor of metalloproteinase 1 (TIMP1), and epithelial-to-mesenchymal transition (EMT) components, in CRC tumors suggesting their potential collaboration to promote EMT and CSCs. TIMP1 is MMP-independent and regulates cell development and apoptosis in various cancer cell types, including CRC. Recent studies showed that TIMP1 cleaves CXCL8 on its chemoattractant, thereby influencing its mechanistic response to therapy. This therefore suggests crosstalk among the c-MYC/CXCL8/TIMP1 oncogenic signatures. In this study, we explored computer simulations through bioinformatics to identify and validate that the MYC/CXCL8/TIMP1 oncogenic signatures are overexpressed in CRC, Moreover, our docking results exhibited putative binding affinities of the above-mentioned oncogenes, with our novel small molecule, RV59, Finally, we demonstrated the anticancer activities of RV59 against NCI human CRC cancer cell lines both as single-dose and dose-dependent treatments, and also demonstrated the MYC/CXCL8/TIMP1 signaling pathway as a potential RV59 drug target.

Section: Introductionmentioning

confidence: 99%

Comprehensive Omics Analysis of a Novel Small-Molecule Inhibitor of Chemoresistant Oncogenic Signatures in Colorectal Cancer Cell with Antitumor Effects

Mokgautsi

et al. 2021

Cells

Self Cite

“…1 H NMR (300 MHz, CDCl 3 ) spectrum is illustrated in S7 Fig . For NSC757963, a solution of NSC745885 (0.5 g, 2 mmol) in glacial acetic acid (15 mL) was treated with HCl (5 mL) at 90°C, potassium chlorate (2 g) was added to the reaction mixture over a period of 45 min then the reaction mixture was kept boiling for 4 h. The product was then precipitated by cooling in an ice bath and crystallized from acetic acid, synthesis steps are summarized in S8 Fig [ 46 ]. NSC757963 was obtained as a yellowish orange powder (yield = 72%).…”

Section: Methodsmentioning

confidence: 99%

Novel Anthra[1,2-c][1,2,5]Thiadiazole-6,11-Diones as Promising Anticancer Lead Compounds: Biological Evaluation, Characterization & Molecular Targets Determination

et al. 2016

Self Cite

The novel compounds NSC745885 and NSC757963 developed at our laboratory were tested against a panel of 60 cancer cell lines at the National Cancer Institute, USA, and a panel of 39 cancer cell lines at the Japanese Foundation of Cancer Research. Both compounds demonstrated selective unique multi-log differential patterns of activity, with GI50 values in the sub-micro molar range against cancer cells rather than normal cardiac cells. NSC757963 showed high selectivity towards the leukemia subpanel. Activities of both compounds strongly correlated to expression of NFKB1 and CSNK2B genes, implying that they may inhibit the NF-κB pathway. Immunocytochemical microscopy of OVCAR-3 cells showed clear cytosolic accumulation of the NF-κB p65 subunit following treatment. Western blotting showed dose dependent inhibition of the nuclear expression of the NF-κB p65 subunit with subsequent accumulation in the cytosol following treatment. Docking experiments showed binding of both compounds to the NF-κB activator IKKβ subunit preventing its translocation to the nucleus. Collectively, these results confirm the ability of our compounds to inhibit the constitutively active NF-κB pathway of OVCAR-3 cells. Furthermore, COMPARE analysis indicated that the activity of NSC757963 is similar to the antituberculosis agent rifamycin SV, this was confirmed by testing the antimycobacterial activity of NSC757963 against Mycobacterium tuberculosis, results revealed potent activity suitable for use in clinical practice. Molecular properties and Lipinski’s parameters predicted acceptable bioavailability properties with no indication of mutagenicity, tumorigenicity, irritability and reproductive effects. Oral absorption experiments using the human Caco-2 model showed high intestinal absorption of NSC745885 by passive transport mechanism with no intestinal efflux or active transport mechanisms. The unique molecular characterization as well as the illustrated anticancer spectra of activity and bioavailability properties warrant further development of our compounds and present a foundation brick in the pre-clinical investigations to implement such compounds in clinical practice.

“…At the same time, 10 μM doxorubicin decreased the viability of SV-HUC-1, WMOY-1 and RWPE-1 cells to 50%, 20%, and 40%, respectively. In prostate cancer DU-145 cells, NSC763968 induced apoptosis and inhibited phosphorylation of ERK and p38 kinases [20]. As both ERK and p38 pathways are involved in the pathogenesis of cancers of different origin [21,22], it is tempting to speculate that NSC763968 treatment inhibits those pathways, which in turn contributes to the anticancer activity of this compound.…”

Section: Derivatives Of 125-thiadiazolementioning

confidence: 99%

Thiadiazole derivatives as anticancer agents

Szeliga

2020

Pharmacol. Rep

In spite of substantial progress made toward understanding cancer pathogenesis, this disease remains one of the leading causes of mortality. Thus, there is an urgent need to develop novel, more effective anticancer therapeutics. Thiadiazole ring is a versatile scaffold widely studied in medicinal chemistry. Mesoionic character of this ring allows thiadiazole-containing compounds to cross cellular membrane and interact strongly with biological targets. Consequently, these compounds exert a broad spectrum of biological activities. This review presents the current state of knowledge on thiadiazole derivatives that demonstrate in vitro and/or in vivo efficacy across the cancer models with an emphasis on targets of action. The influence of the substituent on the compounds’ activity is depicted. Furthermore, the results from clinical trials assessing thiadiazole-containing drugs in cancer patients are summarized.