Synthesis, X-ray crystal structures, stabilities, and in vitro cytotoxic activities of new heteroarylacrylonitriles.
Twenty-three acrylonitriles, substituted at position 2 with either triazoles or benzimidazoles and at position 3 with various substituted furan, thiophene, or phenyl rings, were prepared by Knoevenagel condensation and tested for in vitro cytotoxic potency on 11 human cancer cell lines. X-ray crystal analysis of two representative compounds showed that the olfenic bond is E-configured. Structure-activity-relationships (SAR) indicated that position 2 is flexible for substituents with various nitrogen heterocyclics while position 3 is very sensitive to change; the most potent compounds contained a 5-nitrothiophen-2-yl ring at position 3 and either benzimidazol-2-yl (11) or a 5-benzyl-1H-[1,2,4]-triazol-3-yl (7) group at position 2 of acrylonitrile. SARs for the thiophen-2-yl-benzimidazoles show the following trend for position 5: NO2 >> H > Cl = CH3. Compound 11 was on average 10- and 3-fold more potent than cisplatin and etoposide, respectively. However, the acrylonitrile functionality is not an absolute requirement for cytotoxic activity because replacement of the nitrile group for either a hydrogen or a methyl group also gave active compounds. The acrylonitriles caused delayed cell death characterized by giant cells with multilobed nuclei. Compound 11 was found to bring about the increase in the activities of caspases 3 and 9 in the HL-60 cell line in a manner similar to etoposide, strongly indicating that apoptosis is the mechanism of cell death. The selectivity of various compounds toward cancer cells was estimated by comparing the IC50 values obtained from a noncancerous epithelial cell line, h-TERT-RPE1, with the average IC50 value from the cancer cell lines; 11 showed an average 1.7-fold greater activity toward cancer cells. The stabilities of the new compounds under cell culture conditions, estimated by HPLC, indicated that a major fraction of the compounds were lost from the medium over the first 24 h.
Saczewski
Franciszek
F
Department of Chemical Technology of Drugs, Medical University of Gdańsk, Al. Gen. Hallera 107, 80-416 Gdańsk, Poland. saczew@farmacja.amg.gda.pl
Reszka
Przemyslaw
P
Gdaniec
Maria
M
Grünert
Renate
R
Bednarski
Patrick J
PJ
D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D009842:Oligopeptides; D013876:Thiophenes; C487572:pyridine-2-carboxylic acid (1-(1-(4-bromobenzyloxymethyl)-3-(1-(1-carbamoyl-3-methylbutylcarbamoyl)ethylcarbamoyl)-2-hydroxypropylcarbamoyl)-2-methylpropyl)amide; D000181:Acrylonitrile