A novel hydroxyfuroic acid compound as an insulin receptor activator. Structure and activity relationship of a prenylindole moiety to insulin receptor activation.
BACKGROUND
Diabetes Mellitus is a chronic disease and many patients of which require frequent subcutaneous insulin injection to maintain proper blood glucose levels. Due to the inconvenience of insulin administration, an orally active insulin replacement has long been a prime target for many pharmaceutical companies. Demethylasterriquinone (DMAQ) B1, extracted from tropical fungus, Pseudomassaria sp., has been reported to be an orally effective agent at lowering circulating glucose levels in diabetic (db/db) mice; however, the cytotoxicity associated with the quinone moiety has not been addressed thus far.


METHODS
A series of hydroxyfuroic acid compounds were synthesized and tested for their efficacies at activating human insulin receptor. Cytotoxicity to Chinese hamster ovary cells, selectivities over insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and fibroblast growth factor (FGF) receptors were examined in this study.


CONCLUSIONS
This study reports a new non-quinone DMAQ B1 derivative, a hydroxyfuroic acid compound (D-410639), which is 128 fold less cytotoxic as DMAQ B1 and as potent as compound 2, a DMAQ B1 synthetic derivative from Merck, at activating human insulin receptor. D-410639 has little activation potential on IGF-1 receptor but is a moderate inhibitor to EGF receptor. Structure and activity relationship of the prenylindole moiety to insulin receptor activation is discussed.
Tsai
Henry J
HJ
Pharmaceutical R&D Program, Development Center for Biotechnology, Hsi-Chih City 221, Taiwan, Republic of China. henry_j_tsai@yahoo.com
Chou
Shan-Yen
SY
D000818:Animals; D015703:Antigens, CD; D016466:CHO Cells / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000819:agonists*; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship
D015703:Antigens, CD; C546453:D 410639; D005663:Furans; D007004:Hypoglycemic Agents; D007211:Indoles; C119066:L 783281; D011994:Recombinant Proteins; D066246:ErbB Receptors; C496365:FGFR3 protein, human; C435941:INSR protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D011972:Receptor, Insulin