Synthetic studies and biological activity of Spiro indolizidine-oxindole and indolizidine alkaloids derivative

การศึกษาการสังเคราะห์และการออกฤทธิ์ทางชีวภาพของสไปโรอินโดลิซิดีนออกซินโดลและอินโดลิซิดีนอัลคาลอยด์ที่มีความหลากหลายทางโครงสร้าง

Name: Artid Buaphan

Name: อาทิตย์ บัวผัน

LCSH: Alkaloids -- Synthesis -- Research

LCSH: Organic Chemistry -- Research

LCSH: Indolizidine alkaloids

Abstract: Spiroindolizidine-oxindole and indoloquinolizidine belong to an important class of alkaloids with variety of structures and biological activites. For example, rhynchophylline and mitraphylline, natural product isolated from the plant species Uncaria and Mitragyna speciosa ‘Kratom’ found in the region of Africa and South America and Southeast Asia especially in Thailand. Uncaria have 34 species in the world. In Southeast Asia, some of the traditional treatments for medicinal proposes such as ailments including cardiovascular and central nervous system such as lightheadedness, dizziness, convulsions, numbness and hypertension rely on extracts from Uncaria plants. Another related indolizidine alkaloid is hirsutine, indoloquinolizidine alkaloid isolated from the plant species Hirsutus and Uncaria extraction, which have various biological activities used as a traditional medicine in China to cure convulsions analgesic and a sedative. Especially, hirsutine involved medical community to inhibit the growth of influenza A virus (subtype H3N2) with an EC50 value of 0.40-0.57 µg/mL. Hirsutine is 10-20 times more effective than ribavirin as drug. Our objective of this research is to find ways to synthesize rhynchophylline and hirsutine analog in the form of enamide with functionality suitable for further synthesize spiroindolizidine-oxindole and indoloquinolizidine derivative, respectively. We used oxidative ring contraction and N-acyliminium ion cyclization, cope elimination, hydrogenation, and Micheal reacion as key reactions to construct spiroindolizidine-oxindole and indoloquinolizidine, respectively. Herein we reported the syntheses of spiroindolizidine-oxindole and indoloquinolizidine from commercial L-glutamic acid and tryptamine which have alkoxy instead of enamide that provided a less complication in synthetic route to study a reaction that could be provided for spiroindolizidine-oxindole and indoloquinolizidine derivative synthesis. We used N-acyliminium ion cyclization to construct the indoloquinolizidine for hirsutine analog. The oxidative ring contraction of indoloquinolizidine gave spiroindolizidine-oxindole. The N-dibenzylamino group in spiroindolizidine-oxindole and indoloquinolizidine was removed using cope elimination to provide a cyclic enamide as a key intermediate. Micheal reaction with various alcohol provided series of spiroindolizidine-oxindole] and indoloquinolizidine derivatives. These compounds active by values exhibit nitric oxide synthesis inhibition and induced nitric oxide synthase (iNOS) protein expression. Nitric oxide is an important cellular signaling molecule which is synthesized from L-arginine. It is a vital molecule that affects cell homeostasis in our body controlling movement of smooth muscle, activating innate immunity against some pathogens and triggering the inflammatory process. In part of chemical pretreatment spiroindolizidine-oxindole and indoloquinolizidine significantly reduced active by values iNOS expression. It showed the most significant activity against nitric oxide (NO) production. It seemed like that this chemical could protect inflammation. The series of highly active indoloquinolizidines and spiro[indolizidine-oxindole derivatives were found to be inhibitors of α-glucosidase and therefore are potentially useful for treatment to delay the absorption of glucose after meals. Our synthetic indoloquinolizidines and spiroindolizidine-oxindole derivatives inhibited α-glucosidase with IC50 values between 13.83±0.01 and 900.44±0.01 μM. Among them, the indoloquinolizidine and spiroindolizidine-oxindole derivative displayed strong activity when compared with acarbose as positive control (an IC50 value of 106.09±0.03 μM).

มหาวิทยาลัยศิลปากร. สำนักหอสมุดกลาง

Address: นครปฐม (Nakorn Prathom)

Email: wangthapralibrary@gmail.com

Name: Punlop Kuntiyong

Role: Advisor

Name: พัลลภ คันธิยงค์

Role: อาจารย์ที่ปรึกษาหลัก

Created: 2022

Modified: 2025-06-05

Issued: 2025-06-05

วิทยานิพนธ์/Thesis

application/pdf

eng

DegreeName: Doctor of Philosophy

Level: Doctoral Degree

Descipline: Organic Chemistry

Grantor: Silpakorn University

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