Efficient and regioselective synthesis of -diiodinated homobenzylic alcohol derivatives: evaluation as potential anticancer IDO/TDO inhibitors

• Published in: Organic & biomolecular chemistry 2024-09, Vol.22 (36), p.7395-741
• Main Authors: Al-Zoubi, Raed M, Al-Jammal, Walid K, Shkoor, Mohanad, Bani-Yaseen, Abdulilah D, Khan, Abbas, Agouni, Abdelali, McDonald, Robert
• Format: Article
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d4ob01076k

A simple and direct synthesis of 2,6-diiodophenylethanol building blocks through highly regioselective metalation ( MIE )/oxirane S N 2-type ring opening of 1,2,3-triiodobenzene is described. A significant impact of the nature of the R 1 group on the reactivity of the reaction was discovered but not in terms of site-selectivity. The MIE quenching step is easily controlled by the use of slow-reacting electrophiles "oxiranes" providing solely the ortho -diiodinated homobenzylic alcohol derivatives (internal products) in excellent site-selectivity and with stereoretention. The reaction proceeded without any additives to activate the oxiranes and tolerated a wide range of substrates. The reaction of electron-deficient 1,2,3-triiodoarene systems and neutral oxiranes under the optimized conditions provided the highest isolated yields. The reaction is facile, scalable, efficient, general in scope, and generates handy precursors for further chemical manipulation. In silico interaction analysis revealed that compounds 7a , 7p , 7t and 7z established favourable interactions with the receptors IDO and TDO. Moreover, the molecular simulation results revealed stable dynamics, minimal internal fluctuations, tighter packing and more favourable dynamic features. Furthermore, the 7a -IDO reported a TBE of −26.22 ± 0.24 kcal mol −1 , 7t -TDO reported a TBE of −46.66 ± 0.27 kcal mol −1 , 7p -TDO reported a TBE of −48.02 ± 0.29 kcal mol −1 while 7z -TDO reported a TBE of −48.51 ± 0.28 kcal mol −1 . This shows that these compounds potentially interact with IDO and TDO and consequently cause the inhibition of these targets. Moreover, the BFE results also revealed that this combination suggests that the gas-phase interactions between the components are favorable, but the solvation of the system is unfavorable. In the context of binding, it further means that the protein and ligand have attractive forces when in close proximity as seen in the gas phase, but when solvated, the system experiences an increase in free energy due to interactions with the solvent. This further implies that the binding might be enthalpically favorable due to favorable gas-phase interactions but entropically unfavorable due to unfavorable solvation effects. Our analysis shows that our designed compounds have unmatched pharmacological potential, far surpassing previously reported compounds. This highlights the innovative nature of these derivatives and sets a new benchmark in IDO and TDO drug discovery, i