Synthesis elaboration of fragments that potentially inhibit the HOP-HSP90 protein-protein interaction.

Abstract

Heat Shock Protein 90 (HSP90) is a molecular chaperone that mediates the stability and maturation of many important proteins for oncogenesis. There is an overexpression of the Heat Shock Protein 70/Heat Shock Protein 90 Organising Protein- HSP90 (HOP-HSP90) protein-protein interaction (PPI) complex in tumour tissues unlike in healthy cells. This PPI complex of HSP90 displayed a potential druggable target because of the crucial role it plays in cancer development. However, the challenge is the development of HOP-HSP90 PPI inhibitors. The literature showed the activity of valsartan (27) for the inhibition of HOP-HSP90 PPI as it entails the features of ortho-biphenyl tetrazole fragments that were obtained from the Structural-Binding Relationship (SBR) of the active fragments using fragment-based drug discovery (FBDD). These fragments bound to the tetratricopeptide repeat 2A (TPR2A) domain of HOP and inhibited the PPI of HOP-HSP90. As a result, this study aimed to synthesise and assay ortho-biphenyl tetrazole fragments as inhibitors of HOP-HSP90 for novel anticancer inhibitors, triple-negative breast cancer (TNBC). Valsartan (27) and its analogues were synthesised following reported procedures and modified methods. A series of 13 ortho-biphenyl tetrazole desired fragments were successfully synthesised using a Suzuki-Miyaura cross-coupling reaction and [3 + 2] cycloaddition of nitrile with sodium azide. The cross coupling of 2-iodobenzonitrile or 2-(2-bromophenyl) acetonitrile with para-substituted phenylboronic acid was conducted using different substrates including Cl, Br, F, CH3, CF3, H, and OCH3. Cycloaddition was done after the cross-coupling to skip the protection step of the tetrazole. With the desired ortho-biphenyl tetrazole fragments in hand, the PPI inhibition activity was evaluated at different concentrations from 0 mM to 2.0 mM. It is interesting to observe that some of these fragments showed PPI activity at different concentrations including compounds 76, 80, 82, 83 and 84. No activity was observed following the incorporation of the benzylic carbon. The data presents the successful lead optimisation for the development of HOP-HSP90 novel PPI inhibitors for the treatment of TNBC.

Iqoqa. IHeat Shock Protein 90 (HSP90) iyimolecular chaperone elamula ukuzinza nokuvuthwa kwamaphrotheni amaningi abalulekile e-oncogenesis. Kukhona ukuvezwa ngokweqile kweHeat Shock Protein 70/Heat Shock Protein 90 Organising Protein-HSP90 (HOP-HSP90) inkimbinkimbi yokuxhumana kwamaprotheni, iprotein-protein interaction (PPI) ezimileni okungafani namaseli anempilo. Le nkimbinkimbi ye-PPI ye-HSP90 ibonise ithagethi engase iphuze izidakamizwa ngenxa yendima yayo ebalulekile ekuthuthukisweni komdlavuza. Nokho, inselelo ukwakhiwa kwezivimbeli zama-HOP-HSP90 PPI. Imibhalo iibonisa umsebenzi wevalsartan (27) wokuvinjwa kwe-HOP-HSP90 PPI njengoba ihlanganisa izici zezingcezwana ze-ortho-biphenyl tetrazole ezatholwa kuStructural-Binding Relationship (SBR) yezingcezu ezisebenzayo kusetshenziswa ukutholakala komuthi osuselwe esiqeshini, ifragment-based drug discovery (FBDD). Lezi zingcezu eziboshelwe esizindeni setetratricopeptide esiphinda 2A (TPR2A) se-HOP futhi zavimbela i-PPI ye-HOP-HSP90. Ngenxa yalokho, lolu cwaningo luhlose ukuhlanganisa kanye nokuhlola izingcezu ze-ortho-biphenyl tetrazole njengezivimbeli ze-HOP-HSP90 ezivimbeni zomdlavuza ezinohlonze, umdlavuza webele ophindwe kathathu ubungekho bawo, itriple-negative breast cancer (TNBC). IValsartan (27) nama-analogue ayo ahlanganiswa ngokulandela izinqubo ezibikiwe nezindlela ezilungisiwe. Uchungechunge lwezingcezu eziyi-13 ze-ortho-biphenyl tetrazole ezifiselekayo lwahlanganiswa ngempumelelo kusetshenziswa ukusabela kokuhlangana kweSuzuki-Miyaura kanye ne- [3 + 2] cycloaddition yenitrile ene-azide yesodium. Ukuhlanganisa i-2-iodobenzonitrile noma i-2-(2-bromophenyl) acetonitrile enepara-substituted phenylboronic acid kwenziwe kusetshenziswa amasubstrates ahlukene okuhlanganisa i-Cl, Br, F, CH3, CF3, H, ne-OCH3. I-Cycloaddition yenziwa ngemuva kokuhlanganisana ukuze kweqe isinyathelo sokuvikela setetrazole. Ngezingcezu ezifiselekayo ze-ortho-biphenyl tetrazole esandleni, umsebenzi wokuvimbela we-PPI uhlolwe ngokugxila okuhlukene ukusuka ku-0 mM kuya ku-2.0 mM. Ngentokozo, ezinye zalezi zingcezu zibonise umsebenzi we-PPI ekugxilweni okuhlukene okuhlanganisa amacompounds 76, 80, 82, 83, kanye ne-84. Akukho msebenzi owabonwa ngemuva kokufakwa kwebenzylic carbon. Imininingo yethula impumelelo eholayo yokuthuthukisa isivimbeli esinohlonze se-HOP-HSP90 PPI sokwelapha i-TNBC.