Borylated 2,3,4,5-Tetrachlorophthalimide and Their 2,3,4,5-Tetrachlorobenzamide Analogues: Synthesis, Their Glycosidase Inhibition and Anticancer Properties in View to Boron Neutron Capture Therapy

Abstract

Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7–870 μM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver β-glucosidase and β-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described.

Phthalimides Represent a Promising Scaffold for Multi‐Targeted Anticancer Agents

“…It showed 85–100 % cell growth inhibition at 25 μM concentration. It showed IC 50 values in the range of 3–18 μM against all the ten cancer cell lines [69] …”

Construction of targeted 10B delivery agents and their uptake in gastric and pancreatic cancer cells

“…Neutrons with great kinetic energy will attack 10 B with insufficient neutrons and form 11 B after capturing neutrons, while excessive energy cannot be carried by 11 B, and then decay occurs (1)(2)(3). This process produces highenergy a-particle and 7 Li recoil particle simultaneously release a large amount of energy in a short distance to selectively kill tumor cells (4)(5)(6)(7). BNCT has conducted clinical studies on various diseases, including glioblastoma multiforme, primary and recurrent head and neck cancer, lung cancer, and hepatocarcinoma (8,9).…”

Women in Bioorganic Chemistry

“…The interest in the design and synthesis of novel anticancer therapeutics is also present in the manuscript by Beloglazina and co-workers from Moscow, Russia, who reported the synthesis of a series of S-, O-and Se-containing dispirooxoindoles through 1,3-dipolar cycloaddition of azomethine ylides, assayed their cytotoxicity against different tumor cell lines and performed an in silico study to rationalize the results [7]. The group of Simone and co-workers from Callaghan, Australia, reported the synthesis, glycosidase inhibition and anticancer properties of highly chlorinated benzamide analogues bearing a boronpinacolate ester group, with the perspective to use them in boron neutron capture therapy (BNCT) [8].…”