Rational design of new class of BH3-mimetics as inhibitors of the Bcl-xL protein

The Bcl-2 family of proteins plays an important role in the intrinsic pathway of cell apoptosis. Overexpression of pro-survival members of this family of proteins is often associated with the development of many types of cancer and confers resistance against conventional therapeutic treatments. Accordingly, antagonism of its protective function has emerged as an encouraging anticancer strategy. In the present work, we use a pharmacophore for describing interaction between the BH3 domain of different pro-apoptotic members and the pro-survival protein Bcl-x(L) in order to identify new lead compounds. In the strategy followed in the present work, the pharmacophore was derived from molecular dynamics studies of different Bcl-x(L)/BH3 complexes. This pharmacophore was later used as query for 3D database screening. Hits obtained from the search were computationally assessed, and a subset proposed for in vitro testing. Two of the 15 compounds assayed were found able to disrupt the Bcl-x(L)/Bak(BH3) complex with IC(50) values in the lower micromolar range. Finally, docking studies were performed to explore the binding mode of these compounds to Bcl-x(L) for further modifications.     

Molecular dynamics study of peptide segments of the BH3 domain of the proapoptotic proteins Bak, Bax, Bid and Hrk bound to the Bcl-xL and Bcl-2 proteins

Overexpression of Bcl-2 and Bcl-xL proteins, both inhibitors of apoptosis or programmed cell death, is related to the generation and development of several types of cancer as well as to an elevated resistance to chemotherapeutic treatments. Given that synthetic peptide fragments of the BH3 domain are capable to bind to both proteins and induce apoptosis in cell-free systems and HeLa cells, small molecule non-peptide mimics of these peptides can be considered as a new therapeutic strategy for the treatment of diseases associated to a deficient apoptosis or resistant to the treatments with chemotherapeutic drugs. This strategy is supported by experimental evidences about the death of transformed cells and sensibilization of tumoral cells by the inhibition of the antiapoptotic proteins Bcl-2 and Bcl-xL. In the current work, these proteins complexed with X(16BH3), where X designates the proapoptotic proteins Bak, Bax, Bid and Hrk, have been modeled in order to establish a pharmacophoric hypothesis that must be present in any ligand capable of binding with the antiapoptotic proteins Bcl-2 and Bcl-xL. The pharmacophore is also used to explain the structural features of a set of new small molecule inhibitors of these antiapoptotic proteins.     

NMR solution structure of a photoswitchable apoptosis activating Bak peptide bound to Bcl-xL

The Bcl-2 family of proteins includes the major regulators and effectors of the intrinsic apoptosis pathway. Cancers are frequently formed when activation of the apoptosis mechanism is compromised either by misregulated expression of prosurvival family members or, more frequently, by damage to the regulatory pathways that trigger intrinsic apoptosis. Short peptides derived from the pro-apoptotic members of the Bcl-2 family can activate mechanisms that ultimately lead to cell death. The recent development of photocontrolled peptides that are able to change their conformation and activity upon irradiation with an external light source has provided new tools to target cells for apoptosis induction with temporal and spatial control. Here, we report the first NMR solution structure of a photoswitchable peptide derived from the proapoptotic protein Bak in complex with the antiapoptotic protein Bcl-x(L). This structure provides insight into the molecular mechanism, by which the increased affinity of such photopeptides compared to their native forms is achieved, and offers a rationale for the large differences in the binding affinities between the helical and nonhelical states.     

Biomimetic total synthesis of meiogynin A, an inhibitor of Bcl-xL and Bak interaction

A short, convergent, and selective synthesis of meiogynin A, an inhibitor of the antiapoptotic protein Bcl-xL, has been performed. This synthesis, based on a biomimetic approach, allowed the determination of its absolute configuration. Three isomers of meiogynin A have also been elaborated. One of these was found to be three times more potent than the natural compound.     

Synthesis of conformationally constrained benzoylureas as BH3-mimetics

The design of small molecules that mimic the BH3 domain and bind to Bcl-2 proteins has emerged as a promising approach to discovering novel anti-cancer therapeutics. We reveal the design and synthesis of conformationally constrained benzoylurea scaffolds as conformational probes. Central to helix mimicry, the intramolecular hydrogen bond in the benzoylurea plays a key role in the pre-organisation of the acyclic substrates for cyclisation via ring closing metathesis, providing efficient access to the constrained mimetics.     

Thermochemistry of Lewis adducts of BH3 and nucleophilic substitution of triethylamine on NH3BH3 in tetrahydrofuran

The thermochemistry of the formation of Lewis base adducts of BH(3) in tetrahydrofuran (THF) solution and the gas phase and the kinetics of substitution on ammonia borane by triethylamine are reported. The dative bond energy of Lewis adducts were predicted using density functional theory at the B3LYP/DZVP2 and B3LYP/6-311+G** levels and correlated ab initio molecular orbital theories, including MP2, G3(MP2), and G3(MP2)B3LYP, and compared with available experimental data and accurate CCSD(T)/CBS theory results. The analysis showed that the G3 methods using either the MP2 or the B3LYP geometries reproduce the benchmark results usually to within ~1 kcal/mol. Energies calculated at the MP2/aug-cc-pVTZ level for geometries optimized at the B3LYP/DZVP2 or B3LYP/6-311+G** levels give dative bond energies 2-4 kcal/mol larger than benchmark values. The enthalpies for forming adducts in THF were determined by calorimetry and compared with the calculated energies for the gas phase reaction: THFBH(3) + L → LBH(3) + THF. The formation of NH(3)BH(3) in THF was observed to yield significantly more heat than gas phase dative bond energies predict, consistent with strong solvation of NH(3)BH(3). Substitution of NEt(3) on NH(3)BH(3) is an equilibrium process in THF solution (K ≈ 0.2 at 25 °C). The reaction obeys a reversible bimolecular kinetic rate law with the Arrhenius parameters: log A = 14.7 ± 1.1 and E(a) = 28.1 ± 1.5 kcal/mol. Simulation of the mechanism using the SM8 continuum solvation model shows the reaction most likely proceeds primarily by a classical S(N)2 mechanism.     

Anti and gauche conformers of an inorganic butane analogue, NH3BH2NH2BH3

The crystal structures of an inorganic butane analogue, NH(3)BH(2)NH(2)BH(3) (DDAB), were determined using single crystal X-ray diffraction, revealing both anti and gauche conformations. The anti conformation is stabilized by intermolecular dihydrogen bonds in the crystal whereas two gauche conformations of DDAB observed in its 18-crown-6 adducts are stabilized by an intramolecular dihydrogen bond. The two gauche conformations show rotational isomerization but whether they are a pair of enantiomers is yet to be defined.     

Liquefaction of solid-state BH3NH3 by gaseous NH3

This paper reports for the first time that under ammonia atmosphere, ammonia borane (AB) reversibly absorbs up to at least 6 equiv of NH(3), forming liquid AB(NH(3))(n) (n = 1-6) complexes at 0 °C. Reasonable structures for AB(NH(3))(n) were identified via density functional theory calculations, which indicate that the strong classical hydrogen bond formed between the lone pair of NH(3) and the -NH(3) of AB is the driving force for the absorption of ammonia by AB. By use of the van't Hoff equation, the enthalpy change (ΔH) for AB to absorb one NH(3) was determined to be -2.24 kcal/mol, which is in good agreement with the theoretical calculations. Other organic amines were screened to further confirm the role of the N lone pair; only 1,4-diazabicyclo[2.2.2]octane (DABCO) formed a stable adduct, which X-ray structural analysis showed was the DABCO-BH(3) species. Finally, Raman spectra of AB(NH(3))(n) were collected, and its unique spectral features are also discussed.     

Equilibrium structure and torsional barrier of BH3NH3

Born-Oppenheimer equilibrium structures, r(e)(BO), of the electronic ground state of the borazane (BH3NH3) molecule of C3v point-group symmetry are computed ab initio using the CCSD(T) method with basis sets up to quintuple-zeta quality. Inclusion of the counterpoise correction and extrapolation of the structural parameters to the complete basis set limit yield a best estimate of r(e)(BO) of BH3NH3. The anharmonic force field of BH3NH3, computed at the CCSD(T) level of theory with a basis set of triple-zeta quality, allows the determination of semi-experimental equilibrium rotational constants, which in turn result in a semi-experimental equilibrium structure, r(e)(SE). The r(e)(BO) and r(e)(SE) structures are in excellent agreement, indicating the validity of the methods used for their determination. The empirical mass-dependent structure, r(m)(1), of BH3NH3 is also determined. Although it is inferior in quality to the previous two structures, it is much more accurate than the standard empirical r0 and r(s) structures reported earlier for BH3NH3. The semi-experimental r(e)(SE) as well as the empirical r(m)(1) structures determined are based on experimental ground-state rotational constants available from the literature for nine isotopologues of borazane. The effective barrier to the internal rotation of BH3NH3, a molecule isoelectronic with CH3CH3, has been computed ab initio, employing the focal-point analysis (FPA) approach, to be 699 +/- 11 cm(-1). This compares favorably with an empirical redetermination of the effective barrier based on the above r(e)(SE) structure, V3 = 718(17) cm(-1).     

Molecular mechanism for H2 release from BH3NH3, including the catalytic role of the Lewis acid BH3

Electronic structure calculations using various methods, up to the coupled-cluster CCSD(T) level, in conjunction with the aug-cc-pVnZ basis sets with n = D, T, and Q, extrapolated to the complete basis set limit, show that the borane molecule (BH3) can act as an efficient bifunctional acid-base catalyst in the H2 elimination reactions of XHnYHn systems (X, Y = C, B, N). Such a catalyst is needed as the generation of H2 from isoelectronic ethane and borane amine compounds proceeds with an energy barrier much higher than that of the X-Y bond energy. The asymptotic energy barrier for H2 release is reduced from 36.4 kcal/mol in BH3NH3 to 6.0 kcal/mol with the presence of BH3 relative to the molecular asymptote. The NH3 molecule can also participate in a similar catalytic process but induces a smaller reduction of the energy barrier. The kinetics of these processes was analyzed by both transition-state and RRKM theory. The catalytic effect of BH3 has also been probed by an analysis of the electronic densities of the transition structures using the atom-in-molecule (AIM) and electron localization function (ELF) approaches.     

Stereospecific Polymerization of Isoprene with Nd(BH4)3(THF)3/MgBu2 as Catalyst

Summary: The neodymium trisborohydride Nd(BH₄)₃(THF)₃ (THF = tetrahydrofuran) has been used as a catalyst precursor for isoprene polymerization for the first time. Associated to an excess of Al(Et)₃, the resulting catalyst is moderately active, giving a mixture of cis‐ and trans‐ polymer. Addition of a stoichiometric amount of MgBu₂ to Nd(BH₄)₃(THF)₃ affords a stereospecific catalyst providing trans‐1,4‐polyisoprene, more than 96% regular. That dual component Nd/Mg system also shows a better efficiency and good control of the molecular weights. A molecular structure is tentatively attributed to a bimetallic active species, based on ¹H NMR experiments.

Possible Nd/Al and Nd/Mg active initiating species.     

NH3BH3的双接触蓝移双氢键的理论研究

运用量子化学从头算方法研究了NH3BH3与含大的分子内超共轭的质子给体CHF3, H2CO, HCOOH, HCOCl和HNO形成的双接触弯曲双氢键B—H2…H—X(X＝C, N)的分子结构、电子密度拓扑性质与频率位移特征. 计算结果表明, 在所有体系中, 由于双氢键的形成, B—H键拉长且伸缩振动频率红移, 而X—H键长减小且伸缩频率蓝移. 弯曲的双接触构型导致分子间超共轭减小、X—H键的大的正重极化与正重杂化以及分子内超共轭减小三个因素导致了X—H键蓝移; B—H键红移的主要原因是B—H键的负的重极化与负的重杂化.     

The ab initio limit quartic force field of BH3

The complete quartic force field of BH(3) has been converged to the ab initio limit by extrapolation of core-valence correlation-consistent basis set series (cc-pCVXZ, X = T, Q, 5) of all-electron CCSD(T) (coupled-cluster singles and doubles with perturbative triples) energy points. Additional computations including full coupled-cluster treatments through quadruple excitations (CCSDTQ), scalar relativistic effects, and diagonal Born-Oppenheimer corrections (DBOC) were concurrently executed. Within second-order vibrational perturbation theory (VPT2) our quartic force field yields the fundamental frequencies nu(1) = 2502.3 cm(-1), nu(2) = 1147.2 cm(-1), nu(3) = 2602.1 cm(-1), and nu(4) = 1196.5 cm(-1), in excellent agreement with observed gas-phase fundamentals, displaying a mean absolute error of only 0.3 cm(-1). Our converged prediction for the equilibrium bond length of BH(3) is r(e) = 1.1867 A.     

Fragmental analysis of electronic structure of BH3L molecules

Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of Sciences. Translated from Zhurnal Strukturnoi Khimii, Vol. 33, No. 5, pp. 14–19, September–October, 1992.     

A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles as progesterone receptor antagonists

A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles is reported. Compound (2) prepared by radical cyclisation of (1) was used for the synthesis of racemic and enantiomerically pure 3-asymmetrically substituted oxindoles. Desulfurisation of (2) using Raney Ni yielded the racemate (5). Addition of (S)-1-phenylethanol to compound (2) yielded the diastereoisomer (21) the structure of which was determined using X-ray crystallography. Using a sequence of steps (21) was converted to the enantiomer (8). The enantiomer (9) was similarly prepared from (2) using (R)-1-phenylethanol.     

ChemInform Abstract: Equilibrium Structure and Torsional Barrier of BH3NH3.

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