Synthesis of Disubstituted Triazole and Trisubstituted Triazole Derivatives as HSP90 Inhibitors

Abstract

Heat shock protein 90 (Hsp90) chaperone은 진핵세포 내부에 가장 많이 존재하는 molecular chaperone중 하나로 세포성장, 분화, 생존에 관련된 다양한 단백질들의 안정화 및 활성 조절을 담당한다. Client protein으로 불리는 Hsp90의 기질 단백질에는 50여 가지의 암을 유발하는 단백질들이 포함되어 있는데, Hsp90 활성이 억제될 경우 Hsp90 client protein 들은 proteasome에 의해 분해 된다. 따라서 Hsp90 활성 억제제는 다양한 암 유발 단백질을 동시에 감소시키는 효과를 나타낼 수 있으므로 폭넓은 종류의 암에 적용될 수 있는 항암제로 크게 주목 받고 있다. 본 연구에서는 기존에 개발된 Hsp90 inhibitor인 CCT018159, VER49009, VER51047, NVP-AUY922 (VER52296)들의 구조와 전혀 다른 골격을 가진 새로운 scaffold의 inhibitor를 합성하여, 더 나은 항암 활성을 갖는 물질을 찾고자 하였다. 핵심 합성 전략은 alkyne과 azide를 연결하는 click-iodination 반응과 palladium 촉매 하에서 진행되는 Suzuki cross-coupling 반응이며, 이를 이용하여 핵심 골격인 1,2,3-triazole ring의 1,4,5번 위치에 삼치환된 화합물 20가지와 1,4번 위치에 이치환된 화합물 20가지를 합성하였다. 이렇게 얻어진 총 40가지의 화합물에 대한 세포성장억제 활성을 측정하여 기존의 Hsp90 inhibitor로 알려진 geldanamycin의 활성과 비교하고 새로운 Hsp90 inhibitor로서의 가능성을 확인하였다.;Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. VER-49009 & VER-52296 are kinds of potent compounds among known Hsp90 inhibitors. Especially, VER-52296 has entered clinical trials. Both inhibitors share the common structural feature, resorcinol unit, and bear pyrazole or isoxazole as a key scaffold respectively. We believe 1,4,5-trisubstituted 1,2,3-triazole can be used for a surrogate of pyrazole and isoxazole. Compared to pyrazole and isoxazole as a scaffold of Hsp90 inhibitor, 1,4,5-trisubstituted 1,2,3-triazole has several benefits: i) triazole can retain the hydrophilic and H-bonding interactions in the ligand-enzyme structure due to the N in the similar position to that of pyrazole & isoxazole, ii) triazole has a heteroaromatic ring system, and can hold the same conformation through the same hydrophobic interactions, iii) triazole derivatives can be synthesized in short steps efficiently by using click chemistry. Through click chemistry and Suzuki cross-coupling, we sythesised total 40 compounds as Hsp90 inhibitors (20 compounds of 1,4,5-trisubstituted-1,2,3-triazole sesies and 20 compounds of 1,4-disubstituted-1,2,3-triazole). Among them, some compounds showed potent of inhibition activities. So, our 1,4,5-trisubstituted-1,2,3-triazole focused library can be a good access method for developing novel Hsp90-targeted anticancer agents.