Date of Award

May 2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

James JMC Cook

Committee Members

Alan AWS Schwabacher, Mahmun MMH Hossain, Xiaohua XP Peng, Arsenio AAP Pacheco

Keywords

Benzodiazepine, C(3)-N(4) bond breaking, Indole alkaloid, O-methylmacusine B and 19,20- dihydro - O - methylmacusine B, penta-cyclic ketone, Sarpagine

Abstract

Indole alkaloids are chemically, biologically and commercially significant, as well as diversely distributed important group of natural products. These are of prominence because of their resemblance with various biologically essential molecules including tryptophan, tryptamine, and serotonin. The Sarpagine type indole alkaloids comprise one of the most diverse series of indole alkaloid natural products. These indole alkaloids are primarily isolated from three plant families: Apocynaceae, Rubiaceae, and Loganiaceae which have been used in traditional and folk medicines in many countries around the world. Biological screening of these alkaloids is not always possible, presumably, due to the paucity of the isolated natural products. However, some of the bases from this group of structurally related alkaloids have been shown to possess important biological activity. Considering the useful bioactivity and complex structural features, the total synthesis of these alkaloids is of importance. Some key transformations in our strategy include the diastereospecific asymmetric Pictet-Spengler cyclization, diastereospecific Dieckmann condensation, and an enolate driven palladium catalyzed cross-coupling process. The total synthesis of hystrixnine, gelsempervines A and B were approached with the key challenge of solving the C(3)-N(4) bond breaking of pentacyclic core. But attempts to get into this oxo series were not successful despite many attempts. However, the synthesis of two other target indole alkaloids, O-methylmacusine B and 19,20- dihydro - O - methylmacusine B have also been approached using the enantiospecific Pictet-Spengler reaction as the key chiral step. In the second part, I will show my research on some novel GABAA receptor ligands. Benzodiazepine related compounds are the class of psychoactive drugs which act as a positive allosteric modulator of gamma‑aminobutyric acid type A (GABAA) receptor ion channels. Due to their potent activity, low toxicity, minimal drug-drug interactions in the liver, rapid penetration across the blood-brain barrier (BBB), rapid absorption from the gastrointestinal tract, and ready distribution in the brain, BZDs have been used in the clinic as anxiolytics, sedative-hypnotics, myorelaxants and anticonvulsants for over four decades. The pharmacological action exerted by the BZD depends upon different subunits of the GABAA receptor complex. Throughout the years several GABAA α2/α3 receptor subtype-selective ligand has been developed in Milwaukee for the treatment of epilepsy and chronic pain. Among them KRM-II-81, the bioisostere of lead α2/α3 subtype-selective ligand HZ-166, demonstrated significant anticonvulsant, antinociceptive, antiepileptic and antidepressant efficacy in different rodent models without causing amnesia, sedation, ataxia, or the propensity for addiction/dependence. As a part of the continued search for improved drug with less side effects , some novel bioisosteres of HZ-166 has been synthesized and characterized along with some biological studies due to their strong resemblance with the successful lead candidate KRM-II-81.

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