Synthesis and in vitro anticancer activity evaluation of novel bioreversible phosphate inositol derivatives

• Published in: European journal of medicinal chemistry Vol. 93; pp. 172 - 181
• Main Authors: Chen, Wenbin, Deng, Zhaohui, Chen, Kuangyu, Dou, Daolei, Song, Fanbo, Li, Luyuan, Xi, Zhen
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 26.03.2015; Elsevier
• Subjects: 4-Acyloxybenzyl; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bioreversible protection; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Humans; Inositol Phosphates - chemical synthesis; Inositol Phosphates - chemistry; Inositol Phosphates - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Phosphate inositol; Science & Technology; Structure-Activity Relationship; Bioreversible protection; Anticancer; 4-Acyloxybenzyl; Phosphate inositol; MICROBIAL OXIDATION; PROTECTION; ANALOGS; BIOACTIVATION; LUNG-CANCER CELLS; CA-2+ RELEASE; ADENOPHOSTIN-A; BIOLOGICAL-ACTIVITY; 1,3,4,5-TETRAKISPHOSPHATE; MYOINOSITOL 1,4,5-TRISPHOSPHATE
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.01.064

The chemistry and biology of phosphorylated inositols have become intense areas of research during the last two decades due to their involvement in various cellular signaling processes. However, the metabolic instability by phosphatases or kinases and poor penetration make it difficult to become a drug used in the clinic. The bioreversible protection technique can enhance membrane penetration characteristics and increase the stability of phosphorylated inositols against enzymatic degradation and is applied widely in drug discovery and development. In this paper, we described the design and synthesis of 22 bioreversible phosphotriester inositols, along with the initial antitumor activity results. Most compounds exhibited significant cytotoxic activity against human cancer cell lines A549, MDA-MB-231 and HeLa, but lower cellular toxicity on normal cell MCF10A in comparison with Cisplatin. These compounds can be used as probes to study the mechanism of intracellular signal transduction mediated by phosphate inositol or as leads of phosphate inositol drugs in the clinic. Twenty-two novel bioreversible inositol phosphates derivatives were prepared and most exhibited significant anticancer properties in comparison with the positive control Cisplatin. The preliminary structure–activity relationship was discussed. [Display omitted] •Twenty-two novel bioreversible phosphate inositol derivatives were synthesized.•Synthesized compounds were tested in various human cancer cell lines.•Most compounds exhibited significant anticancer properties, but lower cellular toxicity on normal cell MCF10A.•The higher the degree of phosphorylation, the lower inhibitory activity against human cancer cell lines.•The compounds that phosphorylated at 4-position have the most potent anticancer activity.