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  • Given the overexpression of HO in some tumors

    2022-05-20

    Given the overexpression of HO-1 in some tumors, such as CML, and its potential involvement in chemoresistance to classical chemotherapeutic agents, compounds 4 and 8f were tested in CML cell lines resistant to IM, a classical TK inhibitor used in CML. Compounds 4 and 8f, in combination with IM, showed to be able to overcome IM resistance [55]. Based on these results, the authors designed and synthesized a novel series of hybrid compounds containing in a single chemical entity an IM–like portion able to interact with the TK BCR-ABL (molecular target of IM) and an aryloxybutylimidazol moiety, necessary for HO-1 inhibition, respectively (Table 3) [56]. In the new molecules, the oxybutylimidazole moiety was connected at different positions on the benzamide ring, and the benzamide ring itself was decorated with various substituents (R1). The new compounds were evaluated for both HO-1 and TK inhibition. As reported in Table 3, all hybrids inhibited HO-1 at micromolar concentrations, with IC50s < 1 μM for some of them (9d,e, and 9g) resulting comparable or better to the reference compounds 4, 8f, and Azalanstat. SARs showed that unsubstituted compounds were less potent compared to those carrying a substituent on the benzamide ring (compare 9a–c with 9d–j); among used substituents, a Br tcs products sale at different positions gave the best contribution (9d and 9g). The position of the oxybutylimidazole moiety OR2 was critical for HO-1 inhibition. In fact, with the only exception of compound 9g, the most potent compounds carried this substituent at the 2-position of the benzamide ring (9d–e). Many compounds were more effective than IM itself in inhibiting the other target, TK BCR-ABL, at 10 μM. The remarkable result was that many hybrids interacted with both targets at micromolar concentrations, confirming that it is possible to inhibit both enzymes with one single molecule. Advantages of combining two or more biologically active portions in a single molecule with respect to combination therapy include better patient compliance and reduced side effects due to common drug-drug interactions. In this paper, for the first time, this approach was adopted for HO-1 inhibitors. Compounds 4 and 8f were used as LCs for further SAR studies around the aryloxyalkyl series (Table 4, compounds 10a–c) [57]. The elongation of the connecting alkyl chain and the replacement of the hydrophobic group were investigated. The modification of the central region evidenced a crucial role for the length of the linker. In fact, its elongation from 4 to 5 methylene units afforded oxypentyl derivatives showing an increase of potency towards HO-2 (Fig. 2 and Table 2, Table 4, compare 4 vs 10a and 8f vs 10c); while oxyhexyl derivatives showed a loss of activity towards both HO-1 and HO-2 (Fig. 2 and Table 4, compare 4 vs 10b). In the same paper, the authors investigated how the replacement of the aryloxy moieties with bicyclic heterocyclic nuclei (benzothiazole, 5-chlorobenzothiazole or benzoxazole), influenced the potency of the LCs (Table 4, compounds 11a–d, 12a,b). Overall, benzoxazole, 2-benzoxazolone, and 2-benzothiazolone showed impaired inhibitory activity (compounds 11a and 12a,b), whereas benzothiazole and 5-chlorobenzothiazole series exhibited the most exciting results. Particularly, the thiopropyl derivatives, 11b,c, were powerful HO-1 inhibitors. The elongation of the chain from 3 to 4 methylene residues, while not impacting HO-1 activity resulted in a loss of selectivity towards HO-2 (compare 11b vs. 11c). Also, the presence of a chlorine residue at the 5-position of benzothiazole ring inverted the activity affording a potent and selective HO-2 inhibitor, 11d. This series of compounds represent some among the first potent and selective HO-2 inhibitors described until that time. Noteworthy, although selective HO-2 inhibitors hold different hydrophobic moieties (aryloxy for 10a and 10c, and 5-chlorobenzothiazole for 11d), they possess a five element linking chain, indicating that this length is crucial for the interaction with the different HO isoforms.