Toxicity of (22R,23R)-22,23-dihydroxystigmastane derivatives to cultured cancer cells.
Toxicity of eight 22,23-dihydroxystigmastane derivatives (four pairs of (22R,23R)- and (22S,23S)-isomers differing in steroid backbone structure) to human breast carcinoma MCF-7 cells was compared. For every pair of structurally related compounds, (22R,23R) isomer was found to be significantly more toxic than (22S,23S) isomer. Computational analysis showed that side chain of (22R,23R)-22,23-dihydroxystigmastane derivatives is rigid, whereas that of (22S,23S)-isomers is rather flexible. Structure of steroid backbone significantly affects cytotoxicity of (22R,23R)-22,23-dihydroxystigmastane derivatives to human breast carcinoma MCF-7 cells, human ovary carcinoma CaOv cells, and human prostate carcinoma LnCaP cells. (22R,23R)-3beta,22,23-trihydroxystigmast-5-ene and (22R,23R)-3beta,22,23-trihydroxystigmast-5-en-7-one, both comprising equatorial 3beta-hydroxyl group, exhibited the highest cytotoxicity, while the most polar 28-homobrassinolide and 28-homocastasterone, both comprising 2alpha,3alpha-dihydroxy groups, exhibited the lowest toxicity. Binding of (22R,23R)-22,23-dihydroxystigmastane derivatives to plasmatic membrane was suggested to be important for cytotoxicity.
Misharin
Alexander Yu
AY
V.N. Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
Mehtiev
Arif R
AR
Zhabinskii
Vladimir N
VN
Khripach
Vladimir A
VA
Timofeev
Vladimir P
VP
Tkachev
Yaroslav V
YV
D000970:Antineoplastic Agents / Q000633:toxicity*; D045744:Cell Line, Tumor / Q000187:drug effects*; D002778:Cholestanones / Q000737:chemistry / Q000633:toxicity*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009369:Neoplasms; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002778:Cholestanones; C070163:homobrassinolide; C070164:homocastasterone