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Synthesis and Biological Evaluation of Novel Carbocyclic Nucleosides

Title
Synthesis and Biological Evaluation of Novel Carbocyclic Nucleosides
Authors
DEVIDAS, NAYAK AKSHATA
Issue Date
2014
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
최선
Abstract
Part I. Synthesis, Anti-Renal Fibrosis Activity, and Binding Affinity of Truncated 2-Hexynyl-N6-substituted-(N)-methano-carbanucleosides as A3 Adenosine Receptor Ligands Extracellular adenosine acts as a signaling molecule and regulates many physiological functions by mediating cell signaling through binding to four subtypes (A1, A2A, A2B, and A3) of adenosine receptors (ARs) in our body. On the basis of the structure of adenosine, extensive modifications on the N6 and/or 4′-CH2OH of adenosine have been explored to achieve subtype selectivity, among which a truncated 2-chloro-N6-(3-iodobenzyl)-thioadenosine (Ki = 4.16 nM) was discovered as a potent and species-independent A3AR antagonist. Further, truncated N6-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution was observed to be dual acting A2A and A3 adenosine receptor ligands with potent anti-inflammatory activity. In order to examine if truncated N6-substituted-(N)-methanocarbaadenosine derivatives having 2-hexynyl substituent show the activity similar to that of the corresponding 4'-thioadenosine derivatives, the former was synthesized starting from D-ribose. The functionalization at the C2-position of 6-chloropurine derivatives was achieved via lithiation mediated stannyl transfer and copper-or palladium catalyzed coupling reactions. The N6-metylamino derivative (Ki = 4.19 nM) was discovered as highly selective low efficacy partial antagonist of A3AR. It was found that high binding affinity was retained in A3AR but not in A2AAR. All synthesized compounds were screened for renoprotective effects in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-β1-induced collagen I upregulation, and their A3AR binding affinities were proportional to anti-fibrotic effects; N6-methylamino derivative was most potent (IC50 = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis as well. Part II. Synthesis and Biological Evaluation of 2'-β-Substituted-fluoroneplanocin A Analogues as Antiviral and Anticancer Agents Aristeromycin and neplanocin A are representatives of carbocyclic nucleosides which showed significant broad-spectrum antiviral and antitumor activity. However due to their cytotoxicity to host cells, they could only serve as lead compounds for further development of medicinally potent analogues. From the systemic structure-activity relationship study, fluoroneplanocin A and fluorocyclopentenyl-cytosine have emerged as promising antiviral and antitumor agents. Because modification at C-2′ position have been recognized as important means to further enhance the efficacy, based on these findings, 2'β-substituted fluoroneplanocin A analogs were synthesized and evaluated for their antiviral and anticancer activities against several viruses and tumor cell lines. Selective protection of allylic hydroxyl group, DAST fluorination and Mitsunobu condensation were employed as key steps to obtain the target nucleosides. However, none of the compounds showed any significant activities which might be due to the lack of 2'-hydroxyl group.;Part I. Synthesis, Anti-Renal Fibrosis Activity, and Binding Affinity of Truncated 2-Hexynyl-N6-substituted-(N)-methanocarbanucleosides as A3 Adenosine Receptor Ligands 세포 외 아데노신 은 신체 내 아데노신 수용체 (A1, A2A, A2B, A3)에 결합함으로써 다양한 생리활성을 조절한다. 아데노신 분자 구조에 근거해서, 아데노신 구조에 근거하여 종간-독립적이고 효과적인 A3 아데노신 수용체 길항제를 발견하기 위해서, 아데노신의 N6와 4’-CH2OH를 다른 group으로 치환하여 다른 종류의 아데노신 수용체에 대해서 선택적인 truncated 2-chloro-N6-(3-iodobenzyl)-thioadenosine (Ki = 4.16 nM)를 합성하였다. C2과 C8 위치에 치환체를 가진 truncated N6-substituted-4'-oxo- 과 4'-thioadenosine 유도체는 A2A와 A3 아데노신 수용체에 모두 결합하며 항염증 효과를 나타내었다. 2-hexyl 치환체를 가진 truncated N6-substituted-(N)-methanocarbaadenosine 유도체가 4’-thioadenosine과 비슷한 정도의 활성을 보이는지 확인하기 위해서 그 유도체를 D-ribose로부터 합성하였다. N6-metylamino derivative (Ki = 4.19 nM)는 높은 선택성의 A3 아데노신 수용체 부분 길항제로 밝혀졌다. Lithiation을 경유한 stannyl 이동 반응과 구리/팔라듐 촉매 커플링 반응을 통하여 6-chloropurine의 2번과 6번에 치환체를 도입하였다. 이것은 A3 아데노신 수용체에 대해서는 높은 결합 친화력이 유지가 되었으나 A2A 아데노신 수용체에 대해서는 그렇지 않았다. 모든 합성된 물질은 사람 신장 섬유증 모델의 TGF-β1-stimulated mProx tubular cells 에서 보호효과를 보았다. 대부분의 물질들은 TGF-β1-induced collagen I 의 upregulation을 억제하였다; N6-methylamino 유도체가 가장 효과적 이였고, 이 물질은 신장 섬유증의 치료에 좋은 후보물질이 될 것으로 예상한된다. Part II. Synthesis and Biological Evaluation of 2'-β-Substituted-fluoroneplanocin A Analogues as Anti viral and Anticancer Agents Aristeromycin과 neplanocin A는 대표적인 carbocyclic nucleoside로 광범위 항바이러스, 항암 효과를 가지지만, 숙주 세포에 대한 세포독성 때문에 효과적인 치료제로 개발하는데 한계가 있다. 구조-활성 관계 연구를 통해 fluoroneplanocin A와 fluorocyclopentenyl-cytosine은 유력한 항바러스제, 항암제가 될 가능성이 있음이 밝혀졌다. C-2’ 번 위치를 변경하는 것이 효과를 증대시키는데 중요하기 때문에, 이 사실에 근거하여, 2′β를 치환한 fluoroneplanocin A 유도체를 합성하고, 항바이러스와 항암 효과를 평가했다. 이 타겟 물질을 얻는데 중요한 반응으로 allylic hydroxyl group의 선택적인 protection과 DAST fluorination, Mitsunobu condensation이 수행되었다. 그러나 어떤 물질도 활성을 보이지 않았는데, 아마도 2’-hydroxyl group이 없었기 때문으로 예상된다.
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