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laoshe5932: ½ð±Ò+40, лл£¡ 2015-12-21 08:49:42
Both isomers of 4a and 4b were obtained and reactivity of that of 4a SGLT-2 was within 200 nM, while that of 4b was within 300 nM. In general, the reactivity of this series was not ideal and it was supposed to be the result of the highly strained three-membered ring which is responsible for the  unstability of the compounds leading to deficiency in inhibiting enzyme and thus low reactivity in vitro. Taking the influence of ring strain on stability of the compounds into consideration, less strained four-membered rings were synthesized to observe its inhibition of SGLT-2 enzyme in vitro.
It was easy for the elimination of the hydroxyl of 5a and the hydroxylmethyl of 5c to form carbocation. And carbocation is likely to undergo rearrangement in protic solvents, which may lead to the consequence of losing inhibition of enzyme SGLT-2. It could be concluded from the structure-activity relationship that how hydroxyl affects reactivity was that compounds with hydroxyl were significantly more reactive than those with alkyloxyl, compounds with monohydroxyl are better than those with multiple hydroxyls and inhibition of compounds with one hydroxyl on enzyme decreases along with the increase in the number of C atom.
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vivian-lave

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2Â¥2015-12-16 23:57:29
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laoshe5932

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2Â¥: Originally posted by vivian-lave at 2015-12-16 23:57:29
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3Â¥2015-12-17 08:52:04
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dyn_123

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laoshe5932: ½ð±Ò+20, ¡ïÓаïÖú, ллÄúµÄ·­Òë 2015-12-21 08:50:31
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We got two different isomers namely 4a and 4b simultaneously. The activity of 4a in within 200nM, while 4b within 300nM. This kind of compounds, as a whole, didn't exhibit an ideal activity. And it probably resulted from the relatively strong strain tension of three-membered ring which leaded to the instability of the compounds and low inhibition effect on enzymes, thus demonstrating a bad activity in vitro. Taking the influence of the tension on the compound's stability into consideration, we tried to synthesize four-membered ring compounds which incorporated a relatively small tension in order to further check on the inhibition effect on SGLT-2 in vitro.

The methyl group on 5a as well as the hydroxymethyl group on 5c are good leaving groups, giving rise to carbon cations. And in protonic solvent, the cations perhaps will rearrange to generate corresponding products, which may result in the failure to inhibit SGLT-2.  It can be told that the existence of hydroxyl group exerted an impact no the activity in the light of SAR. Compounds with hydroxyl groups showed fat better activities than the ones without hydroxyl groups, while compounds with only one hydroxyl group showed better activities than the ones with more than one hydroxyl groups. In addition, as the number of carbon atoms increased, the inhibition effect of mono hydroxyl compounds on SGLT-2 got weaker and weaker.
5Â¥2015-12-17 18:01:17
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