title: Combination of amino acid/dipeptide with ligustrazine-betulinic acid as antitumor agents.
abstract: The lead compound TBA, 3β-Hydroxy-lup-20(29)-ene-28-oic acid-3, 5, 6-trimethylpyrazin-2-methyl ester, which exhibited promising antitumor activity and induced tumor cell apoptosis in various cancer cell lines, had previously been reported. Moreover, reports have revealed that the introduction of amino acid to betulinic acid could improve selective cytotoxicity as well as water solubility. Thus, a series of novel TBA amino acid and dipeptide derivatives were designed, synthesized and screened for selective cytotoxic activity against five cancer cell lines (HepG2, HT-29, Hela, BCG-823 and A549) and the not malignant cell line MDCK by standard MTT assay. Most of the tested TBA-amino acid and dipeptide analogues showed stronger anti-proliferative activity against all tested tumor cell lines than TBA. Among them, BA-25 exhibited the greatest cytotoxic activity on tumor cell lines (mean IC50= 2.31 ± 0.78 μM), that was twofold than the positive drug cisplatin (DDP), while it showed lower cytotoxicity on MDCK cell line than DDP. Further cell apoptosis analyses indicated BA-25-induced apoptosis was associated with loss of mitochondrial membrane potential and increase of intracellular free Ca2+concentration.
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Wen-Qiang
authors.initials: WQ
authors.lastname: Yan
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Gao-Rong
authors.initials: GR
authors.lastname: Wu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Chen-Ze
authors.initials: CZ
authors.lastname: Zhang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Yao-Tian
authors.initials: YT
authors.lastname: Han
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Fu-Hao
authors.initials: FH
authors.lastname: Chu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. Electronic address: wpl581@126.com.
authors.forename: Peng-Long
authors.initials: PL
authors.lastname: Wang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. Electronic address: hm_lei@126.com.
authors.forename: Hai-Min
authors.initials: HM
authors.lastname: Lei
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology; D000840:Anisoles; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053978:Pentacyclic Triterpenes; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D000596:Amino Acids; D000840:Anisoles; D000970:Antineoplastic Agents; D004151:Dipeptides; D053978:Pentacyclic Triterpenes; D011719:Pyrazines; D014315:Triterpenes; C484217:2,4,6-tribromoanisole; D002118:Calcium; C017953:tetramethylpyrazine; D000094062:Betulinic Acid
keywords: Amino acids derivatives; Apoptosis; Betulinic acid; Dipeptide derivatives; Selective cytotoxicity; Structure-activity relationships