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Abstract
The dihydropyranoindole scaffold was identified as a promising target for improving the anti-cancer activity of HDAC inhibitors from the preliminary screening of a library of compounds. A suitable methodology has been developed for the preparation of novel dihydropyranoindoles via the Hemetsberger indole synthesis using azido-phenylacrylates, derived from the reaction of corresponding alkynyl-benzaldehydes with methyl azidoacetate, followed by thermal cyclization in high boiling solvents. Anti-cancer activity of all the newly synthesized compounds was evaluated against the SH-SY5Y and Kelly neuroblastoma cells as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Biological studies showed that the tetracyclic systems had significant cytotoxic activity at higher concentration against the neuroblastoma cancer cells. More importantly, these systems, at the lower concentration, considerably enhanced the SAHA toxicity. In addition to that, the toxicity of designated systems on the healthy human cells was found to be significantly less than the cancer cells.
Highlights
Chemotherapy is one of the most widely used treatments for high-risk cancer patients [1,2]
The studies presented in this study have contributed to the investigation of the potential of dihydropyranoindoles to act as Suberoylanilide hydroxamic acid (SAHA) enhancers for the treatment of neuroblastoma and breast cancer cells
The desired tricyclic and tetracyclic dihydropyranoindoles was achieved by the reaction of corresponding hydroxybenzaldehydes with haloalkynes followed by the application of the Hemetsberger indole synthesis to yield the related indoles
Summary
Chemotherapy is one of the most widely used treatments for high-risk cancer patients [1,2]. A range of well-known agents, namely Doxorubicin, Cyclophosphamide, Etoposide have been used to combat various cancers in modern chemotherapeutic therapy [3,4]. A major problem faced in chemotherapy is resistance to commonly-used anti-cancer drugs [5]. Development of novel anti-cancer chemotherapeutic agents is of utmost importance in the area of drug discovery and development. The histone deacetylase (HDAC) inhibitors are a class of chemotherapeutic agents that hold promise in cancer therapy [6,7]. HDAC inhibitors have been reported to suppress cell proliferation and angiogenesis, induce cell differentiation and promote apoptosis in a number of cancer cell types [8,9]
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