PubMed · 9174812
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J Geller. 1997. Benign prostatic hypertrophy.. https://pubmed.ncbi.nlm.nih.gov/9174812/
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The structure-activity relationship of flavonoids as inhibitors of xanthine oxidase and as scavengers of the superoxide radical, produced by the action of the enzyme xanthine oxidase, was investigated. The hydroxyl groups at C-5 and C-7 and the double bond between C-2 and C-3 were essential for a high inhibitory activity on xanthine oxidase. Flavones showed slightly higher inhibitory activity than flavonols. All flavonoid derivatives except isorhamnetin (30) were less active than the original compounds. For a high superoxide scavenging activity on the other hand, a hydroxyl group at C-3' in ring B and at C-3 were essential. According to their effect on xanthine oxidase and as superoxide scavengers, the flavonoids could be classified into six groups: superoxide scavengers without inhibitory activity on xanthine oxidase (category A), xanthine oxidase inhibitors without any additional superoxide scavenging activity (category B), xanthine oxidase inhibitors with an additional superoxide scavenging activity (category C), xanthine oxidase inhibitors with an additional pro-oxidant effect on the production of superoxide (category D), flavonoids with a marginal effect on xanthine oxidase but with a prooxidant effect on the production of superoxide (category E), and finally, flavonoids with no effect on xanthine oxidase or superoxide (category F).
The effects of various inhibitors on the glial cell line-derived neurotrophic factor (GDNF)-induced neurite formation in TGW human neuroblastoma cells were investigated. Treatment of cells with Ser/Thr protein kinase inhibitors such as staurosporine, H-7, H-8 and HA-1004, induced neurite formation without GDNF. On the other hand, tyrosine kinase inhibitors such as erbstatin, genistein and herbimycin A did not produce neurites per se, but effectively enhanced the GDNF-induced neurite formation. A phosphatase inhibitor, okadaic acid, and Ras inhibitors such as oxanosine, damnacanthal and conophylline strongly suppressed the effect of GDNF. These results suggest that a tyrosine protein kinase has a suppressive role in the neurite formation induced by GDNF and that Ras is necessary for the signaling initiated by GDNF.
Previously, we have described inhibition of HIV-1 infection by T30177, 5'-(GTGGTGGGTGGGTGGGT)-3', an oligonucleotide that is a potent inhibitor of HIV-1 integrase in vitro (Mazumder et al. (1996) Biochemistry 35, 13762). Here a family of oligonucleotides, analogs of T30177, has been studied. On the basis of thermal denaturation, we show that a folded structure of T30177 is much more stable than that of the thrombin binding aptamer, which only differs with T30177 in the loop sequence. Sequence changes reveal that loop interactions are solely responsible for this observed stability difference. In the presence of K+ ion, the fold of T30695, a designed 16mer derivative, is indeed more stable than T30177. Loop folding within T30695 is very ion selective. Quantitative analysis of thermal denaturation suggests that the loops of T30695, 5'-(GGGTGGGTGGGTGGGT)-3', and T30177 confer the ability to coordinate three equivalents of K+ ion (one bound to the core octet and two bound to the loops); however, the thrombin binding aptamer is shown to bind only one K+ equivalent. Folding kinetics and CD titration demonstrate that K+-induced folding of T30695 and T30177 is a two-step process, consistent with a sequential model in which a first equivalent of K+ binds to the octet core, followed by slow K+-induced rearrangement of the loop domains. Comparing structural stability with the capacity of the folded oligomers to inhibit the HIV-1 integrase enzyme in vitro or HIV-1 infection in cell culture, we have found that the folding and activity data are highly correlated, suggesting that formation of an orderly, ion-coordinated loop structure similar to that in T30177 or T30695 may be a prerequisite for both integrase inhibition and anti-HIV-1 activity.