Novel N-(3-carboxyl-9-benzyl-carboline-1-yl)ethylamino acids: synthesis, anti-proliferation activity and two-step-course of intercalation with calf thymus DNA.
To explore the intercalating mechanism of -carbolines, four novel N-(3-carboxyl-9-benzyl-carboline-1-yl)ethylamino acids [-phenylalanine (6a), -alanine (6b), -isoleucine (6c) and -glycine (6d)] were prepared here. Their in vitro anticancer activities were examined by their anti-proliferation for 5 human carcinoma cell lines. The average IC50s against 5 human carcinoma cell lines are 53.54 microM, 118.77 microM, 147.34 microM and greater than 291.63 microM for 6a, 6b, 6c and 6d, respectively. The DNA intercalating mechanism of 6a-d was approved by the comparison of the parameters and signals of UV, CD and fluorescence spectra of calf thymus DNA (CT DNA) alone and the CT DNA/6a-d system. Using fluorescence titration based kinetic analysis a two-step-course consisting of stacking and intercalating was described and the stacking was considered as the key step to the CT DNA intercalating mechanism of 6a-d. Using fluorescence titration based thermomechanical analysis, the stacking complexes of 6a-d with CT DNA were described to be formed spontaneously and to be stabilized predominantly by their hydrophobic interactions. The intercalation itself goes very fast and only has limited contribution to their anticancer activities.
Wu
Jianhui
J
College of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. China.
Cui
Guohui
G
Zhao
Ming
M
Cui
Chunying
C
Peng
Shiqi
S
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy*; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism / Q000379:methods; D004247:DNA / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008968:Molecular Conformation; D013050:Spectrometry, Fluorescence / Q000379:methods; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D002243:Carbolines; D007364:Intercalating Agents; D004247:DNA; C427203:calf thymus DNA