Bisbenzimidazoles: Anticancer Vacuolar (H⁺)-ATPase Inhibitors

Small molecule chemotherapeutic agents such as Imatinib, Gefitinib, and Erlotinib have played a significant role in the treatment of cancer. Although the unprecedented progress has been achieved in cancer treatment with these targeted agents, there is a strong demand for the development of selective and highly efficacious cancer drugs. V-ATPases are emerging as important target for the identification of novel therapeutic agents for cancer. Our screening and drug discovery processes have identified the bisbenzimidazole derivative (RP-15) as a potent anticancer V-ATPase inhibitor. In the present study, bisbenzimidazoles (compound-25, RP-11 and RP-15) have been tested for proton-pump inhibition activity in human hepatoma cell line (Huh7.5). RP-15 displayed comparable proton-pump inhibition activity to the standard Bafilomycin A1. We examined the antiproliferative activity of these analogs in two highly invasive and metastatic inflammatory breast cancer (IBC) cell lines (SUM 149PT and SUM190PT) along with Huh7.5. The compound-25 (SUM190PT: IC50 = 0.43±0.11 μM) and its structural analog RP-11 (SUM190PT: IC50 = 0.49±0.09 μM) have shown significant inhibition toward IBC cell lines. Additionally, RP-11 and RP-15 have demonstrated very good cytotoxicity toward the majority of cancer cell lines in the NCI 60 cell line panel

Synthesis and biological activities of new 3,5-disubstituted -2-( ethyl-5'-thioxo-1',3',4'-oxadiazol-4'-ethylacetate-2'-yl)indoles,-2-(5'- thioxo-1',3',4'-oxadiazol-4'methylcarboxyhydrazide-2'-yl) indoles and -2-(5'- thioxo-1',3', 4'-oxadiazol-4'alkyl- 2'-yl) indoles

76-82<span style="font-size:14.0pt;mso-bidi-font-size:9.0pt; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">3,5-Disubstituted indole-2-carboxylates 1 a-g are reacted with hydrazine hydrate to furnish the corresponding indole-2-carboxyhydrazides 2a-g These on reaction with alkaline carbon disulphide under thermal reaction  conditions produce respective 2-(5'-thioxo-1',3',4'-oxadiazol-2'-yl<span style="font-size:13.0pt;mso-bidi-font-size:8.0pt;font-family:Arial;mso-fareast-font-family: " times="" new="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">) <span style="font-size:14.0pt;mso-bidi-font-size: 9.0pt;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">indoles 3a-g. Reaction of 3a-g with ethyl chloroacetate and alkyl halides in dry acetone and anhyd, K<span style="font-size:12.0pt; mso-bidi-font-size:6.0pt;font-family:" times="" new="" roman";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">2<span style="font-size:14.0pt; mso-bidi-font-size:9.0pt;font-family:" times="" new="" roman";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">CO<span style="font-size:11.0pt; mso-bidi-font-size:6.0pt;font-family:" times="" new="" roman";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">3<span style="font-size:11.0pt; mso-bidi-font-size:6.0pt;font-family:" times="" new="" roman";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"=""> <span style="font-size:14.0pt;mso-bidi-font-size: 9.0pt;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">yield indoles 4a-g and 6a-r, respectively. Compounds 4a-g on further reaction with hydrazine hydrate in ethanol afforded the compounds 5a-g. Compounds synthesised have been screened for their biological activities.</span

Large Conductance, Calcium Activated Potassium (BK) Channels as New Therapeutic Target for Glioma

Gliomas are the most common malignant primary brain tumors that arise within the central nervous sys-tem in adults and they account for more than 80% of all brain tumors (Central Brain Tumor Registry of the United States [CBTRUS] http://www.cbtrus.org/). These tumors remain difficult to treat because of the infiltrative growth of the tumor cells, and their resist-ance to standard therapy. Glioblastoma Multiforme (WHO grade IV) is the most aggressive of the gliomas, accounts for nearly 60-70% of malignant gliomas. A common approach for the treatment of GBM involves surgery, radiation therapy, and various chemotherapeu-tic regimens [1,2]. Despite advance standard therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Even patients who are optimally treated with combined multimodal treatments have a median survival of only 12 months. This is possibly because of the poor drug delivery and the correspondingly lim-ited therapeutic response caused by partly intact blood brain barrier (BBB) and blood-tumor barrier (BTB)

Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents

Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10 μM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile

Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents

Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10 μM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile

Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H+)-ATPase Inhibitors

The vacuolar (H+)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I–IV). Based on the initial hit (V), we designed and synthesized a focused set of novel bisbenzimidazole analogs (2a–e). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative (2e) is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC50 = 0.04 ± 0.02 μM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound 2e could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment

Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipaseD activity, which leads to generation of the growth-factor-like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4-tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues block ATX activity with Ki values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed-mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers invitro in a dose-dependent manner. The average terminal half-life for compound 22 is 10±5.4h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30b significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The 4-substituted benzylphosphonic acids and 6-substituted naphthalen-2-ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX-LPA-LPAR axis both invitro and invivo. Inhibiting the ATX-LPA-LPAR axis: New 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues were synthesized, and the most potent ATX inhibitors, 22 and 30b, show outstanding invivo profiles by diminishing lung metastases of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment model. These two lead compounds effectively inhibit the ATX-LPA-LPAR axis both invitro and invivo. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim