Novel alkylphospholipid-DTC hybrids as promising agents against endocrine related cancers acting via modulation of Akt-pathway

• Published in: European journal of medicinal chemistry 2014-10, Vol.85, p.638-647
• Main Authors: Jangir, Santosh, Bala, Veenu, Lal, Nand, Kumar, Lalit, Sarswat, Amit, Kumar, Amit, Hamidullah, Saini, Karan S., Sharma, Vikas, Verma, Vikas, Maikhuri, Jagdamba P., Konwar, Rituraj, Gupta, Gopal, Sharma, Vishnu L.
• Format: Article
• Language: English
• Subjects: Akt-pathway; Alkylphospholipid; Anti-proliferative agent; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Breast Neoplasms - pathology; Cell Cycle - drug effects; Cell Line, Tumor; Dithiocarbamate; Ditiocarb - chemistry; Drug Screening Assays, Antitumor; Endocrine cancer; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Membrane Potential, Mitochondrial - drug effects; Miltefosine; Phospholipids - chemistry; Phospholipids - pharmacology; Phosphorylation - drug effects; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.08.028

A new series of 2-(alkoxy(hydroxy)phosphoryloxy)ethyl dialkylcarbodithioate derivatives was synthesized and evaluated against endocrine related cancers, acting via modulation of Akt-pathway. Eighteen compounds were active at 7.24–100 μM against MDA-MB-231 or MCF-7 cell lines of breast cancer. Three compounds (14, 18 and 22) were active against MCF-7 cells at IC50 significantly better than miltefosine and most of the compounds were less toxic towards non-cancer cell lines, HEK-293. On the other hand, twelve compounds exhibited cell growth inhibiting activity against prostate cancer cell lines, either PC-3 or DU-145 at 14.69–95.20 μM. While nine of these were active against both cell lines. The most promising compounds 14 and 18 were about two and five fold more active than miltefosine against DU-145 and MCF-7 cell lines respectively and significantly down regulated phospho-Akt. Possibly anti-cancer and pro-apoptotic activity was mostly due to blockade of Akt-pathway. Alkylphospholipid-DTC hybrids designed & tested against endocrine related cancers. Two compounds were 2–5 times active than miltefosine against DU-145 and MCF-7 cells. Compounds acted via Akt-pathway blockade. [Display omitted] •Alkylphospholipid-DTC hybrids designed & tested against endocrine related cancers.•Two compounds were 2–5 times active than miltefosine against DU-145 and MCF-7 cells.•Anti-cancer and pro-apoptotic activity was mostly due to blockade of Akt-pathway.•Interestingly these compounds were less toxic towards non-cancer cells, HEK-293.