title: Novel alkylphospholipid-DTC hybrids as promising agents against endocrine related cancers acting via modulation of Akt-pathway.
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.
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Jangir
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific & Innovative Research, New Delhi 110001, India.
authors.forename: Veenu
authors.initials: V
authors.lastname: Bala
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Nand
authors.initials: N
authors.lastname: Lal
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Sarswat
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.lastname: Hamidullah
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Karan S
authors.initials: KS
authors.lastname: Saini
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Verma
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific & Innovative Research, New Delhi 110001, India. Electronic address: vlscdri1@rediffmail.com.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004050:Ditiocarb / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010743:Phospholipids / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010743:Phospholipids; D004050:Ditiocarb; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt-pathway; Alkylphospholipid; Anti-proliferative agent; Dithiocarbamate; Endocrine cancer; Miltefosine