Synthesis, Anti‐tubulin and Antiproliferative SAR of Steroidomimetic Dihydroisoquinolinones

Abstract

A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)-based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ core was connected to methoxyaryl D-ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one (16 g): GI50 51 nm in DU-145 cells). The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nm. Furthermore, 6-hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (16 f) and 16 g and their sulfamate derivatives 17 f and 17 g (2-(3,5-dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one and 7-methoxy-2-(3,4,5-trimethoxybenzoyl)-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A-4, and bind competitively at the colchicine binding site of tubulin. Compounds 16 f and 17 f were also shown to demonstrate in vitro anti-angiogenic activity. Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a “steroid-like” conformation that may partially explain the excellent in vitro activities.

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

“…1,2,3,4-Tetrahydroisoquinoline (THIQ) motifs are present in many natural alkaloids [ 1 ]. THIQ derivatives have also been investigated as potential therapeutics in a wide range of diseases and recent studies have explored their potential as steroidomimetics [ 2 – 5 ]. Given the success of these authors in designing highly potent non-steroidal chimeric microtubule disruptors based upon decorated THIQ-based mimics of the steroidal AB ring system that possess pendant N- substituents [ 2 ], robust routes to direct N- aryl substituted THIQs were targeted for related activities ( Fig.…”

Recent Advances in Synthesis of 3,4‐Dihydroisoquinolin‐1(2H)‐one

“…Use of the strong acid in high concentration led to the formation of carbamate dicataion, which is dissociated to the protonated isocyanate which further cyclized to 3,4-dihydroisoquinolin-1(2H)-one (Scheme 1). [24] Additionally, the same research group demonstrated that the phenyl ethyl carbamate bearing ortho salicylate (13) as an ether group accelerates the rate for the formation of the protonated isocyanate which underwent subsequent electrophilic cyclization to 3,4-dihydroisoquinolin-1(2H)-one. They found out ortho salicylate helps in accelerating the CÀ O bond dissociation which facilitates the formation of the isocyanate cation.…”

“…3,4-Dihydroisoquinolin-1(2H)-one core containing compounds possess wide range of biological activities such as anti-HIV, [7] antidepressant, [8] anticancer, [9] H3 receptor antagonist for treatment of neuropathic pain, [10] EZH2 inhibitor, [11] PARP inhibitor, [12] steroidomimetic, [13] cyclin-dependent kinase inhibitor, [14] anti-hypertension, anti-arrhythmia, antioxidant, [15] inhibitor of cholesterol biosynthesis, [16] anti-thrombotic, [17] antiinflammatory, [8] antibacterial, [18] PET imaging of s2 receptors. [19] The molecular structure of representative 3,4-dihydroisoquinolin-1(2H)-one's of biological importance is illustrated in Figure 3.…”

Synthesis of C3/C1-Substituted Tetrahydroisoquinolines

“…For example, the antitubulin and antiproliferative activities of C3/C1-substituted THIQs 9 ( Figure 2) depend on the pharmacophore group at C6 (as free phenol or sulfamate group) [32][33][34]. Therefore, procedures of the benzyl protection/deprotection of phenolic groups have been employed in the literature showing in many cases some incompatibility with the other functional groups present on the THIQ skeleton [33].…”