Theoretical Studies On Structures, Electronic Properties And Functional Features Of Several Boron Compounds Used In Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a promising therapeuticmodality for the treatment of malignant brain tumors, but still experimentalcancer treatment method. The successful performance of BNCT depends, toa large extent, on how nonradioactive 10B can efficiently target malignantcells to obtain maximal tumor-to-blood (T/B) ratios during neutronirradiation. Although a vast array of 10B-enriched compounds has beenprepared and tested for efficacy, the clinical trials have been limited to two,sodium mercaptoundecahydrododecaborate (BSH) and p-boronophenylala-nine (BPA). However, the mechanism for selective uptake of BSH and BPAare not so clear despite that they have been used in the clinical trial forBNCT. A relationship between the molecular structure and biologicalproperty of a biologically active compound has been mentioned frequently,but it seems that a clear-cut relationship has been obtained in very few cases.Actually, little information exists as to the structural of the BNCT agentsand their functional features. Knowing the structural and functional featuresof these boron rich compounds is very important in the design of new andpossibly more effective agents. It is obvious that an intensive investigationis needed to explain theoretically the function of BNCT agents at themolecular level, while the exploration of the structural and electronicproperties for these boron-containing compounds is its initial step.Reported here are the computational results on the geometrical andelectronic structures of BSH, BPA, closo-dodecacarborane and their analogs.The geometries, atomic population analyses of the complexes, and thecompositions of some frontier molecular orbitals have been extensivelyinvestigated. These theoretical results are valuable for understanding of thefunctional features for boron-containing compounds used in boron neutroncapture therapy. In this paper, results of Density Functional Theory (DFT)calculations on the BSH analogs, isomers of BPA, cascade polyol-attachedp-BPA derivatives, complex of p-BPA with fructose, and o-dodecacar-borane isonitrile analogs will be presented with the general aim of providingdetailed information on the bonding and structure in these boron-containingspecies.The article is organized as follows. After a brief outline of thecomputational methods used in this study in Section 2, Section 3 presentsresults obtained for optimized geometries, analyses of atomic populationsand frontier molecular orbitals for BSH, BSSB, and BS under investigationusing B3LYP method with the 6-31G(d) basis set. An attempt has beenmade to elucidate the mechanism of the reaction of free radical BS withmodel compound S2(CH3)2 at B3LYP/6-31G(d)// QCISD/6-31G(d) level.The calculations supported the experimental observations that BSH may beoxidized to form dimer BSSB;the dimeric structure readily undergoeshomolytic cleavage, under acidic conditions, generating a free radical BS.Atomic population analyses indicated that the redox reactions proceedthrough intramolecular electronic transfer. Analyses of the frontier orbitalsrevealed that sulfur atom is an active site of the complexes, and BS is thereactive species among BSH, BSSB, and BS. The investigation ofmechanism of the reaction BS+S2(CH3)2 verified that the active BS canattack the disulfide bond of the specific protein. It seem that BS isresponsible for enhancement of the content of 10B atom in the tumor forboron neutron capture therapy.Section 4 presents results obtained for geometrical and electronicstructures of isomers of BPA and polyol-attached p-BPA dericatives atB3LYP/6-31G(d) level. The calculations show that the HOMO and LUMOof p-BPA are located at the C atoms in benzene ring. Analyses of the frontierorbitals reveal that C, N, O atoms, which are located at the coalescentlocation between polyols and p-BPA moieties, are main active sites ofp-BPA derivatives. It seem, compare with p-BPA, that the HOMO featuresare one of main factors of effective biological properties for thepolyol-attached p-BPA derivatives used in boron neutron capture therapytests. The LUMO of BPA(OH),BPA(OH)2 and BPA(OH)4 are similar to theone of p-BPA. It is indicated that the cascade polyol have no impact to thepharmic functions of the p-BPA derivatives for boron neutron capturetherapy tests.In Section 5 the computed results on the geometrical and electronicstructures of p-BPA–fructose complexes are discussed in detail atNPA-PBE1PBE/6-31G**. The structural and electronic properties ofcomplex Ⅰ, Ⅱ, and Ⅲ, considered as possible configuration models forBPA–fructose complexes, and p-boronophenylalanine molecule arecompared. Complex Ⅰ and Ⅱ are the most active among calculatedcompounds, and they are also highly polar molecules comparing with BPAand Ⅲ. The structural feature of complex Ⅲ is less affected by attachingthe fructose. According to the present calculations, it seems that the fructosemoiety contributes activator function to the complex Ⅰ and Ⅱ.Finally, the geometrical and electronic structures of o-C2B10H12 and itsisonitrile analogs are discussed and compared with experiment atB3LYP/6-31G(d) level. For o-C2B10H12 and its isonitrile analog 1, theoptimized bond lengths are found to be quite similar with the usableexperimental values. The orbital components calculated show that theHOMO and LUMO of o-C2B10H11NC and o-C2B10H11CH2NC are σ-bonding,π-bonding and π-antibonding characters resulted from the p-orbital overlapbetween B3 (C3), N, C4 atoms, respectively, but these orbital distributingcharacters of o-C2B10H11CH2NC are cannot compare with o-C2B10H11NC.For the o-C2B10H11NC and o-C2B10H11CH2NC, the C4 atoms can be linkedwith some of transition metal atoms by the coordinate link, respectively. It isnoticed that the calculated HOMO-LUMO energy gap of o-C2B10H11NC isless than that of o-C2B10H11CH2NC and o-C2B10H12, indicating that it ismost reactive among studied systems. The molecular polarities ofo-C2B10H11NC and o-C2B10H11CH2NC are less than of the o-C2B10H12,indicating that there is disadvantage for these isonitrile analogs used inboron neutron capture therapy.The structural features studied in this paper provide a valuable insightinto the properties of boron-containing compounds used in boron neutroncapture therapy. Theoretical results are valuable for understanding of themechanism for selective uptake of these compounds and developing newBNCT agent in the future work.