title: L-1416, a novel MDR reversing agent with possible reduced calcium antagonism.
abstract: BACKGROUND
  Multidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and supposed to be implicated in the resistance to tumor chemotherapy. However, currently none of P-gp inhibitors has been approved by Food and Drug Administration not only due to toxicity but also lack of efficacy in clinical trials.
  
  
  METHODS
  To solve the problem, our lab synthesized a novel compound named 1416 [1-(2,6-dimethylphenoxy)-3,4-dimethoxyphenylethylamino) propane hydrochloride] with the hope of high P-gp inhibition and low side effects. Caco-2 cell monolayer and tumor bearing mice were used to evaluate the P-gp inhibition of 1416 in vitro and in vivo, respectively. One of its potential side effects, calcium antagonism was also evaluated.
  
  
  RESULTS
  Results showed that 1416 showed a similar P-gp inhibition as verapamil in Caco-2 cell monolayer. No significant difference was observed in antitumor enhancement when the optical isomers of 1416 (D-1416 and L-1416) were co-administered with vinblastine. In calcium antagonism, L-1416 showed less calcium inhibition than both D-1416 and verapamil.
  
  
  CONCLUSIONS
  The novel compound 1416 could significantly increase the antitumor effects of cytotoxic drugs and one of its optical isomers, L-1416, might be more promising due to its potential low calcium antagonism.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Zaigang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zyhu@live.com.
authors.forename: Zheyi
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. Electronic address: wuj@nju.edu.cn.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. Electronic address: huyiqiao@nju.edu.cn.
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011437:Propylamines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013237:Stereoisomerism; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
chemical_list: C000602790:1-(2,6-dimethylphenoxy)-3,4-dimethoxyphenylethylamino)propane; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010627:Phenethylamines; D011437:Propylamines; D014747:Vinblastine; D014700:Verapamil; D002118:Calcium
keywords: Calcium antagonism; L-1416; P-gp inhibitor; Tumor therapy