Latent inhibitors. Part 7. Inhibition of dihydro-orotate dehydrogenase by spirocyclopropanobarbiturates

Abstract

A series of 5-spirocyclopropanobarbiturates bearing alkyl and aryl su bstituents on the cyclopropane ring has been synthesized. Dihydro-orotate dehydrogenase from Clostridium oroticum was shown to be inhibited by these compounds. A related series of 5-membered-ring compounds (hydantoins and pyrazoles) was prepared but all the compounds were found to be inactive. In order to correlate these observations with previous resu Its concerning 5arylmet hy I hydantoi ns and 5aryl idenehydantoins as inhibitors, 5-arylidenebarbiturates were also assessed as inhibitors and found t o be the most active of the compounds investigated. The results are interpreted in the context of molecular recognition by this enzyme and the possibility of using substrate surrogates as templates for constructing latent inhibitors of enzymes.

Domino Cyclodimerization of Indole‐Derived Donor–Acceptor Cyclopropanes: One‐Step Construction of the Pentaleno[1,6‐a,b]indole Skeleton

“…Reagent cyclopropanes 1 are readily available from the corresponding indole-3-carbaldehydes through a standard synthetic sequence of Knoevenagel/Corey-Chaykovsky reactions. [10] These cyclopropanes have low stability at elevated temperatures and on silica gel, but can be isolated as pure materials by chromatography on neutral alumina. N-Ben-A C H T U N G T R E N N U N G zylindoles 1 were found to be more stable during storage than their N-methyl analogues.…”

Synthesis of new 4,4-spirocycloalkenic 1,2-diphenylpyrazolidine-3,5-dione derivatives by ring-closing metathesis reactions

“…Автори [4] синтезували 1,2-діазоловий спіран -1-фенілпіразолідин-4-спіроциклопропан-3,5-діон 3, який може виступати інгібітором ферменту ди-гідрооротатдегідрогенази, проте в літературі від-сутні відомості про ненасичені спіроциклічні по-хідні піразолідин-3,5-діонів.…”

“…Попередній комп'ютерний прогноз біологіч-ної активності продуктів метатезису 9а-і за допо-могою програми Prediction of Аctivity Spectra for Substances [5] дозволяє зробити припущення, що одержані сполуки з високою ймовірністю (70-85%) можуть бути інгібіторами L-глутамат оксидази, інгібіторами тестостерон-17бета-дегідрогенази (НАДФ+), антагоністами нікотин альфа2бета2 ре-цептора, протизапальними засобами.…”

Synthesis and biological evaluation of some new spiro derivatives of barbituric acid

“…Several spiro-barbituric acid derivatives in which the 5 th carbon of barbituric acid is substituted by an unsubstituted cyclobutane or cyclohexane ring [11] have been synthesized, but no pharmacological data is obtained with these compounds. Certain spiro compounds have been reported to possess diverse biological activities that include narcotic [12 -13], hypotensive, skeletal muscle relaxant, analgesic [14], anticonvulsant, CNS depressant [15], anti-inflammatory activity [16].…”