4-Amidinoindan-1-one 2'-amidinohydrazone: a new potent and selective inhibitor of S-Adenosylmethionine decarboxylase.
Two isomeric amidino-2-acetylpyridine amidinohydrazones, 11 and 12, and 4-amidinoindanone amidinohydrazone, 17, have been synthesized and tested for inhibition of S-adenosylmethionine decarboxylase (SAMDC) and diamine oxidase and for antiproliferative activity against T24 human bladder carcinoma cells. Compound 11 inhibited SAMDC with an IC50 of 10 nM and was 140- and > 500-fold more potent than methylglyoxal bis(guanylhydrazone) (MGBG) and 12, respectively. The difference in potency between 11 and 12 was interpreted with the help of molecular modeling and appeared to be associated with two different low-energy conformations of the compounds. Compound 17 which represents a conformationally constrained analogue of 11, was superior to the latter and MGBG with respect to selective inhibition of SAMDC and antiproliferative activity, and is of interest as a potential anticancer agent and a drug for the treatment of protozoal and Pneumocystis carinii infections.
Stanek
J
J
Research Laboratory, Ciba-Geigy AG, Basel, Switzerland.
Caravatti
G
G
Frei
J
J
Furet
P
P
Mett
H
H
Schneider
P
P
Regenass
U
U
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000578:Amidines; D006835:Hydrazones; D007189:Indans; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D012437:Adenosylmethionine Decarboxylase