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

  • Eur J Med Chem. 2014 Oct 6:85:638-47. doi: 10.1016/j.ejmech.2014.08.028.
Santosh Jangir  1 ,  Veenu Bala  2 ,  Nand Lal  1 ,  Lalit Kumar  1 ,  Amit Sarswat  1 ,  Amit Kumar  3 ,  Hamidullah  3 ,  Karan S Saini  3 ,  Vikas Sharma  3 ,  Vikas Verma  3 ,  Jagdamba P Maikhuri  3 ,  Rituraj Konwar  3 ,  Gopal Gupta  3 ,  Vishnu L Sharma  4
Affiliations
  • 1. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 2. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific & Innovative Research, New Delhi 110001, India.
  • 3. Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 4. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific & Innovative Research, New Delhi 110001, India. Electronic address: [email protected].
PMID: 25128666 DOI: 10.1016/j.ejmech.2014.08.028
Abstract

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.

Keywords
Akt-pathway; Alkylphospholipid; Anti-proliferative agent; Dithiocarbamate; Endocrine cancer; Miltefosine.