Molecular structure, pKa, lipophilicity, solubility, absorption, polar surface area, and blood brain barrier penetration of some antiangiogenic agents

Abstract

The methods of theoretical chemistry have been used to elucidate molecular properties of selected and novel antiangiogenic agents (semaxanib, sunitinib, N-methylsunitinib, sorafenib, motesanib, ABT-869, vatalanib, vandetanib, AEE 788, CP-547632, A-1, A-2, A-3, and A-4). The geometries and energies of these drugs have been computed using HF/6-31G(d), Becke3LYP/6-31G(d) and Becke3LYP/ 6-31??G(d,p) model chemistries. Wherever possible the most stable conformations of inhibitors studied are stabilized by means of intramolecular hydrogen bonds. Water has a remarkable effect on the geometry of the antiangiogenic agents studied. Computed partition coefficients (ALOGPS method) varied between 2.3 and 5. Compounds studied are described as lipophilic inhibitors. Semaxanib is inhibitor with lowest lipophilicity. The antiangiogenic agents studied are only slightly soluble in water; their computed solubility (log S) from interval between -3.4 and -5.4 is sufficient for fast absorption. Selection criteria for drug-like properties of VEGFR2 inhibitors investigated were designed. Based on these criteria, three compounds (A-2, A-3, and A-4) were selected for synthesis and biological testing for antianiogenic activity on VEGFR2 receptor.

Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth

“…Figure 1B depicts the MS features as well as some key properties for all SANs. Although the lipophilicity of sunitinib variants (SANs 1-5) was decreased compared with sunitinib, the polar surface area remained unaffected (<100 Å 2 ) for all SANs, a parameter known to influence cell membrane permeability (35). A representative mass spectrum and LC/MS-MS chromatogram for a chosen analogue (SAN1) can be found in Supplementary Information Section S2.…”

Interplay of thermochemistry and Structural Chemistry, the Journal (volume 22, 2011, issues 1–3) and the discipline

“…In the following study, Remko et al [172] used ab initio methods to study molecular structure, lipophilicity, solubility, absorption, and blood-brain barrier penetration of some novel antiangiogenic agents (semaxanib, sunitinib, N-methylsunitinib, sorafenib, motesanib, ABT-869, vatalanib, vandetanib, AEE 788, CP-547632, A-1, A-2, A-3, and A-4). The results show that, whenever possible, the most stable conformers are stabilized by intramolecular hydrogen bonds.…”

In silico evaluation of logD7.4 and comparison with other prediction methods

“…Additionally, several studies have reported the effect of lipophilicity on biological activities and transport properties [1][2][3][4][5][6][7], indicating the importance to evaluate the lipophilicity of new drugs or pro-drugs. Thus, an eligible drug usually needs to keep a balance between lipophilicity and hydrophilicity to dissolve in the body fluid and penetrate the biofilm effectively.…”

“…The lipophilicity of a compound can be quantitatively characterized by the partition coefficient (its logarithm form is denoted as logP) or the distribution coefficient (its logarithm form is denoted as logD) if ionized molecular species are present [4,5]. Partition coefficient [8] is the equilibrium concentration ratio of the solute between two immiscible solvents (e.g., n-octanol and water).…”