Discovery of Potent EGFR Inhibitors through the Incorporation of a 3D‐Aromatic‐Boron‐Rich‐Cluster into the 4‐Anilinoquinazoline Scaffold: Potential Drugs for Glioma Treatment

Abstract

New 1,7-closo-carboranylanilinoquinazoline hybrids have been identified as EGFR inhibitors, one of them with higher affinity than the parent compound erlotinib. The comparative docking analysis with compounds bearing bioisoster-substructures, demonstrated the relevance of the 3D aromatic-boron-rich moiety for interacting into the EGFR ATP binding region. The capability to accumulate in glioma cells, the ability to cross the blood-brain barrier and the stability on simulated biological conditions, render these molecules as lead compounds for further structural modifications to obtain dual action drugs to treat glioblastoma.

Medicinal Chemistry of Boron-Bearing Compounds for BNCT- Glioma Treatment: Current Challenges and Perspectives

“…Thereby, we hybridized the 4-anilinoquinazolinyl PTKs and the carboranes as boron delivery pharmacophores, i.e., 71 and 72 (Figure 16) [94]. Especially, hybrid 71 demonstrated 3.3 times higher activity against C6 glioma cells than the parent drug erlotinib (Figure 16), lower cytotoxic effects on normal glia cells, excellent PTK inhibition, capability to accumulate in glioma cells, ability to cross BBB, and stability on simulated biological conditions [94,95].…”

Preparation of dendritic carboranyl glycoconjugates as potential anticancer therapeutics

“…Traditionally icosahedral carboranes have been used to synthesize boron delivery platforms for the treatment of cancer via boron neutron capture therapy (BNCT). 5,6 For an effective boron neutron capture therapy, the required number of 10 B atoms has been estimated to be 10 9 per tumor tissue, which is approximately 35 mg boron per g of tumor tissue. But the surrounding healthy cells must not contain more than 5 mg boron per g of tumor tissue to avoid the damage caused by the radiation to normal healthy cells.…”

“…8 Derivatives of icosahedral carboranes have also shown cytotoxicity towards glioma cells. 9,10 Therefore, derivatives of carborane could be suitable as chemotherapy agents for treatment of cancer. Carboranes are very favorably used for boron delivery because of their high boron content and stability to catabolism.…”

Ruthenium carboranyl complexes with 2,2′-bipyridine derivatives for potential bimodal therapy application

“…The icosahedral closo-C 2 B 10 H 12 carborane 22 and metallacarborane 23 [M(C 2 B 9 H 11 ) 2 ] À clusters are 3D aromatic moieties, possessing high symmetry and stability, 24 and generally low cytotoxicity, 25,26 being good candidates for BNCT. 25,[27][28][29] In this frame, several compositions for potential BNCT applications have been developed, [30][31][32][33][34][35] including high boron-loaded DNA-oligomers, 36 periphery-decorated and core-initiated borane polyanionic macromolecules, 37 peptide-cobalt bis(dicarbollide) conjugates, 38 nucleoside-boron cluster conjugates 39,40 and cholesterol-metallacarborane conjugates, 41 among others.…”