Bimodal Therapeutic Agents Against Glioblastoma, One of the Most Lethal Forms of Cancer

Abstract

About 95 %o fp eopled iagnosed with glioblastoma die within five years. Glioblastoma is the mosta ggressivec entraln ervous systemt umour.I ti sn ecessary to make progress in the glioblastoma treatments ot hat advanced chemotherapy drugs or radiationt herapy or,i deally,t wo-in-one hybrid systems should be implemented.T yrosine kinase receptors-inhibitors and boron neutron capture therapy (BNCT), together,c ould provide at herapeutic strategy. In this work,s unitinibdecorated-carborane hybrids were prepared and biologically evaluatedi dentifying excellent antitumoral-and BNCT-agents. One of the selected hybrids was studieda gainst glioma-cells and found to be 4times more cytotoxic than sunitinib and 1.7 times more effectivet han 10 B-boronophenylalanine fructose complex when the cells were irradiated with neutrons.

Sunitinib-Containing Carborane Pharmacophore with the Ability to Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, Exhibits Powerful In Vivo Anti-Glioblastoma Activity

“…Recently, we designed a series of hybrid compounds ( Figure 2), which combine substructures derived from Sun and icosahedral boron clusters [22], to be tested as bifunctional-boron-cluster-based compounds with relevant activities in cells expressing tyrosine kinase proteins. The substituent at the C-3-indol system and the indolin-2-one motive are important for effective kinase inhibition by Sun.…”

“…The unique rigid and spherical form of the carborane cluster plus the possibility it offers to produce these weak intramolecular interactions could provide extra beneficial interactions with target receptors. Consequently, in the new hybrid compounds (Sun + boron-cluster), the carborane cage could be located in the target-pocket exploring unique regions of chemical space , i.e., in the Sun indolin-2-one region, establishing extra-interactions with kinases that cannot be achieved with purely organic compounds [22]. Two types of substructures-(i) flexible and polar backbones (methyl-1,2,3-triazolylalkyl moieties), and (ii) a rigid and hydrophobic system (2-propynylphenylmethyl linker)-have been selected as connectors between indolin-2-one system and carborane clusters.…”

“…Further, the in vitro activity of the bifunctional-boron-cluster-based compounds (1, 4-11) against different tyrosine kinase-overexpressing tumor cells HT-29, C6, and U98 MG, was evaluated (see Table S1) [22]. Hybrid 1 was the most active against U87 MG glioblastoma cells of the full Sun-boron-cluster-based compound (1, 4-11) series and was at least four times more active than the parent Sun.…”

“…All these indications foresee BNCT as an accessible leading-edge technology. (Sun), erlotinib (Erl), and lapatinib (Lap); and a previous hybrid TKI-boron cluster [18][19][20][21][22].…”

“…Regarding this subject, we have previously investigated and developed hybrid agents that provide dual therapeutic actions (chemotherapy plus BNCT), i.e., tyrosine kinase receptor inhibitors such as chemotherapeutics and boron clusters, as BNCT agents. The substructures derived of the TKRs inhibitors, which were combined with icosahedral boron clusters for potential use in BNCT, are sunitinib (Sun, Figure 1), erlotinib (Erl, Figure 1), and lapatinib (Lap, Figure 1) [18][19][20][21][22].…”