Methylangelicins: structure activity studies on the role of methyl groups present in 3,4 and 4',5' photoreactive sites.
The effect of the introduction of one, two or three methyl groups at the level of 3,4 or 4',5' photoreactive site of angelicin, in terms of extent of intercalation and DNA-photobinding, was studied. The introduction of one methyl group both in the 3 or 4 and in 4' or 5' position increases the affinity of angelicin toward DNA for the molecular complex formation and enhances the DNA-photobinding, even if to a different extent. The increase is more pronounced for occupancy of 5' or 4' position; much less pronounced is the enhancement in the case of 3 or 4 positions. The introduction of two methyl groups in 3,4 or in 4',5' positions leads to an increased capacity to form the intercalated complex with DNA; the photoreactivity is also enhanced, but to a larger extent for 4',5'-dimethylangelicin. No steric hindrance, therefore, seems to be exerted by the introduction of one or two methyl groups at the level of the photoreactive sites of angelicin. The introduction of a third methyl group in 4',5'-dimethyl or in 3,4-dimethylangelicin exhibits a strong enhancement of the DNA photobinding; in particular 4,4',5'-trimethylangelicin appears the most photoreactive towards DNA. Angelicins carrying methyl groups in 3,4 positions exhibit lower antiproliferative activity than derivatives carrying methyl groups in 4',5' positions. No correlation was observed between antiproliferative activity and DNA-photobinding; may be that the presence of methyl groups in 3,4 or in 4',5' positions affects the type of cycloadducts formed. The different ratio of adducts may affect the antiproliferative effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Vedaldi
D
D
Department of Pharmaceutical Sciences, University of Padova, Italy.
Dall'Acqua
F
F
Baccichetti
F
F
Carlassare
F
F
Bordin
F
F
Rodighiero
P
P
Manzini
P
P
Guiotto
A
A
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003956:Dialysis; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry; D009153:Mutagens / Q000737:chemistry; D010777:Photochemistry; D010787:Photosensitivity Disorders / Q000139:chemically induced / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013604:T-Phages / Q000187:drug effects; D014867:Water
D004273:DNA, Neoplasm; D011564:Furocoumarins; D007364:Intercalating Agents; D009153:Mutagens; D014867:Water; C031824:4-methylangelicin; C023026:5-methylangelicin; D004247:DNA