Novel Anthra[1,2-c][1,2,5]Thiadiazole-6,11-Diones as Promising Anticancer Lead Compounds: Biological Evaluation, Characterization & Molecular Targets Determination.
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.
Molecular and Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Ahmed Atef Ahmed
AA
Ali
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Yu-Ru
YR
Lee
Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Tsung-Chih
TC
Chen
Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Chun-Liang
CL
Chen
Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Chia-Chung
CC
Lee
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Chia-Yang
CY
Shiau
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Chiao-Hsi
CH
Chiang
Molecular and Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Hsu-Shan
HS
Huang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D015398:Signal Transduction; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D000995:Antitubercular Agents; C498143:RELA protein, human; D013830:Thiadiazoles; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase