The discovery of novel imidazo[1,2-a]pyridine derivatives as covalent anticancer agents.

The success of targeted covalent inhibitors (TCIs) for treating cancers has spurred the search for novel scaffolds to install covalent warheads. In our endeavour, using a scaffold hopping strategy, we managed to utilize imidazo[1,2-a]pyridine as the core backbone and explored its potential for the development of covalent inhibitors, therefore, synthesizing a series of novel KRAS G12C inhibitors facilitated by the Groebke-Blackburn-Bienaymè reaction (GBB reaction). Preliminary bio-evaluation screening delivered compound I-11 as a potent anticancer agent for KRAS G12C-mutated NCI-H358 cells, whose effects were further clarified by a series of cellular, biochemical, and molecular docking experiments. These results not only indicate the potential of compound I-11 as a lead compound for the treatment of intractable cancers, but also validate the unique role of imidazo[1,2-a]pyridine as a novel scaffold suitable for the discovery of covalent anticancer agents.

Deciphering the Diversified Metabolic Behavior of Hydroxyalkyl Ferrocidiphenols as Anticancer Complexes.

Ferrocidiphenols possessing appropriate substituents in the aliphatic chain have very promising anticancer properties, but a systematic approach to deciphering their diversified metabolic behavior has so far been lacking. Herein, we show that a series of novel ferrocidiphenols bearing different hydroxyalkyl substituents exhibit strong anticancer activity as revealed in a range of in vitro and in vivo experiments. Moreover, they display diversified oxidative transformation profiles very distinct from those of previous complexes, shown by the use of chemical and enzymatic methods and in cellulo and in vivo metabolism studies. In view of this phenomenon, unprecedented chemo-evolutionary sequences that connect all the ferrocidiphenol-related intermediates and analogues have been established. In addition, a comprehensive density functional theory (DFT) study has been performed to decipher the metabolic diversification profiles of these complexes and demonstrate the delicate modulation of carbenium ions by the ferrocenyl moiety, via either α- or ß-positional participation.

Synthesis and bioactivity evaluation of ferrocene-based hydroxamic acids as selective histone deacetylase 6 inhibitors.

Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes and emerges as a promising target for treating cancer and neurodegenerative diseases. Benefited from the unique sandwich conformation of ferrocene, a series of ferrocene-based hydroxamic acids have been developed as novel HDAC6 inhibitors in this paper, especially the two ansa-ferrocenyl complexes with IC50s at the nanomolar level. [3]-Ferrocenophane hydroxamic acid analog II-5 displays the most potent inhibitory activity on HDAC6 and establishes remarkable selectivity towards other HDAC isoforms. Compound II-5 dose-dependently induces accumulation of acetylated α-tubulin while having a negligible effect on the level of acetylated Histone H3, confirming its isoform selectivity. Further biological evaluation of II-5 on cancer cells corroborates its antiproliferative effect, which mainly contributed to the induction of cellular apoptosis. It is worth noting that compound II-5 demonstrates an optimal profile on human plasma stability. These results strengthen ferrocene's unique role in developing selective protein inhibitors and indicate that compound II-5 may be a suitable lead for further evaluation and development for treating HDAC6-associated disorders and diseases.

Structures and electronic properties of M2C2 @ C78 (M = Ti, Zr, Hf): a density functional theory study.

A systematic DFT investigation has been conducted to explore the structures and electronic properties of the metal-carbide endofullerenes M2C2 @ C78 (M = Ti, Zr, Hf) at the PBE/DNP level of theory. The theoretical calculations predicted the following: (i) this series of endofullerenes have the valence states [M4+]2C2(2-) @ C78(6-) (ii) the structure of the [M2C2](6+) cluster encapsulated in the C78(6-) (D3h) cage varies with the increasing of the ionic radius of M4+, i.e., from a linear M-C [triple bond] C-M geometry for M = Ti, through a zigzag geometry for M = Hf to a side-on binding mode for M = Zr; (iii) M2C2 @ C78 (M = Zr, Hf) should display interesting intramolecular dynamic behavior at room temperature, i.e., the encapsulated C2(2-) moiety can rotate freely around the C3-axis of the C78(6-) (D3h) cage; (iv) the [Ti2C2]6+ in the lightest Ti2C2 @ C78 is far more fixed by adopting the linear Ti-C - C-Ti geometry; (v) the order for their ionization potentials is Ti2C2 @ C78 < Hf2C2 @ C78 << Zr2C2 @ C78, whereas their EAs follow the order: Ti2C2 @ C78 < Hf2C2 @ C78 approximately Zr2C2 @ C78. The predicted redox properties of these endofullerenes suggest that Zr2C2 @ C78 is synthetically as approachable as Hf2C2 @ C78.

Sidewall epoxidation of single-walled carbon nanotubes: a theoretical prediction.

[reaction: see text] By means of a two-layered ONIOM approach, we predict that sidewall epoxidation of single-walled carbon nanotubes (SWNTs) with dioxiranes is viable. The SWNT epoxides thus produced could be precursors for further chemical modification of SWNTs, given the abundant and well-established chemistry of organic epoxides. This opens the door for routine chemical manipulation of SWNTs.

Organic functionalization of the sidewalls of carbon nanotubes by diels-alder reactions: a theoretical prediction.

[structure: see text] The viability of the Diels-Alder (DA) cycloaddition of conjugated dienes onto the sidewalls of single-wall carbon nanotubes is assessed by means of a two-layered ONIOM(B3LYP/6-31G:AM1) approach. Whereas the DA reaction of 1,3-butadiene on the sidewall of an armchair (5,5) nanotube is found to be unfavorable, the cycloaddition of quinodimethane is predicted to be viable due to the aromaticity stabilization at the corresponding transition states and products.

What definitively controls the photochemical activity of methylbenzonitriles and methylanisoles? Insights from theory.

CASPT2//CASSCF and B3LYP methodologies have been used to study the excited-state properties and photochemical isomerizations of p-, m-, and o-methylbenzonitriles and methylanisoles. Calculations show that the biradical mechanism is the most favored channel for the photoinduced interconversion of p-, m- and o-methylbenzonitriles, both dynamically and thermodynamically. The formation of biradical as a key intermediate is highly selective, and only the biradicals with a turned-up cyano-substituted carbon are involved in photoisomerization. Methylanisole isomers are inactive relative to methylbenzonitriles at 254 nm. Such remarkable activity difference between methylbenzonitrile and methylanisole in photochemistry arises from the accessibility of the S1/S0 conical intersection as well as the stability of prefulvene biradicals. For methylanisoles, the S1/S0 precursor and the reactive biradicals are inaccessible at 254 nm, which should be the origin of inactivity. The results suggest that the conical intersection accessibility plays a crucial role in the photochemistry of substituted benzenes at 254 nm.

Computational characterization of low-lying states and intramolecular charge transfers in N-phenylpyrrole and the planar-rigidized fluorazene.

Low-lying states and intramolecular charge transfers in N-phenylpyrrole (PP) and its planar-rigidized derivative fluorazene (FPP) have been investigated by ab initio methodologies. On the basis of calculations, properties of the excited states and plausible dual-fluorescence mechanisms have been elucidated. Present results show that S2 as a key state is involved in the consecutive photophysical processes. The S2 state is easily populated under excitation. In the polar MeCN solution, S2 can evolve to either a lower-energy locally excited state or a lower-energy solvated intramolecular charge-transfer state (S-ICT). The former emits a normal fluorescence back to the ground state, and the latter is exclusively responsible for the red-shifted fluorescence band. Calculations reveal that the emissive ICT states in both FPP and PP have similar geometric features, an elongated N-phenyl bond, a pyramidal carbon atom linking the pyrrole ring, and a quinonoid phenyl ring. The twisting of molecule around the N-phenyl bond is not necessary for the intramolecular charge transfer. Predicted absorption and emission spectra are in reasonable agreement with the experimental observations.

Computational analyses of singlet-singlet and singlet-triplet transitions in mononuclear gold-capped carbon-rich conjugated complexes.

Density functional theory and CASSCF calculations have been used to determine equilibrium geometries and vibrational frequencies of metal-capped one-dimensional pi-conjugated complexes (H3P)Au(C[triple chemical bond]C)(n)(Ph) (n = 1-6), (H3P)Au(C[triple chemical bond]CC6H4)(C[triple chemical bond]CPh), and H3P--Au(C[triple chemical bond]CC6H4)C[triple chemical bond]CAu--PH3 in their ground states and selected low-lying pi(pi)* excited states. Vertical excitation energies for spin-allowed singlet-singlet and spin-forbidden singlet-triplet transitions determined by the time-dependent density functional theory show good agreement with available experimental observations. Calculations indicate that the lowest energy 3(pi(pi)*) excited state is unlikely populated by the direct electronic excitation, while the low-lying singlet and triplet states, slightly higher in energy than the lowest triplet state, are easily accessible by the excitation light used in experiments. A series of radiationless transitions among related excited states yield the lowest 3(pi(pi)*) state, which has enough long lifetimes to exhibit its photochemical reactivities.

Theoretical study of photoinduced singlet and triplet excited states of 4-dimethylaminobenzonitrile and its derivatives.

Singlet and triplet low-lying states of the 4-dimethylaminobenzonitrile and its derivatives have been studied by the density functional theory and ab initio methodologies. Calculations reveal that the existence of the methyl groups in the phenyl ring and the amino twisting significantly modify properties of their excited states. A twisted singlet intramolecular charge-transfer state can be accessed through decay of the second planar singlet excited state with charge-transfer character along the amino twisting coordinate or by an intramolecular charge-transfer reaction involved with a locally first excited singlet state. Plausible charge-transfer triplet states and intersystem crossing processes among singlet and triplet states have been explored by spin-orbit coupling calculations. The intersystem crossing process was predicted to be the dominant deactivation channel of the photoexcited 4-dimethylaminobenzonitrile.

XMVB: a program for ab initio nonorthogonal valence bond computations.

An ab initio nonorthogonal valence bond program, called XMVB, is described in this article. The XMVB package uses Heitler-London-Slater-Pauling (HLSP) functions as state functions, and calculations can be performed with either all independent state functions for a molecule or preferably a few selected important state functions. Both our proposed paired-permanent-determinant approach and conventional Slater determinant expansion algorithm are implemented for the evaluation of the Hamiltonian and overlap matrix elements among VB functions. XMVB contains the capabilities of valence bond self-consistent field (VBSCF), breathing orbital valence bond (BOVB), and valence bond configuration interaction (VBCI) computations. The VB orbitals, used to construct VB functions, can be defined flexibly in the calculations depending on particular applications and focused problems, and they may be strictly localized, delocalized, or bonded-distorted (semidelocalized). The parallel version of XMVB based on MPI (Message Passing Interface) is also available.

Steric strain versus hyperconjugative stabilization in ethane congeners.

Rotation barriers in the group IVB ethane congeners H(3)X-YH(3) (X, Y = C, Si, Ge, Sn, Pb) have been systematically studied and deciphered using the ab initio valence bond theory in terms of the steric strain and hyperconjugation effect. Our results show that in all cases the rotation barriers are dominated by the steric repulsion whereas the hyperconjugative interaction between the X-H bond orbitals and the vicinal Y-H antibond orbitals (and vice versa) plays a secondary role, although indeed the hyperconjugation effect favors staggered structures. By the independent estimations of the hyperconjugative and steric interactions in the process of rotations, we found that the structural effect which mainly refers to the central X-Y bond relaxation makes a small contribution to the rotational barriers. Therefore, we conclude that both the rigid and fully relaxed rotations in the group IVB ethane congeners H(3)X-YH(3) observe the same mechanism which is governed by the conventional steric repulsion.

Origins of Rotational Barriers in Hydrogen Peroxide and Hydrazine.

Compared with their isoelectronic system ethane, both hydrogen peroxide and hydrazine exhibit a double well torsional energy curve where skew conformers are favored over trans conformers and cis conformers are energy-maximum states. Clearly, the involvement of the lone oxygen and nitrogen pairs, or more specifically, the enhanced stabilizing n→σ* negative hyperconjugation effect and destabilizing repulsion among lone pairs, complicates the conformational analysis. In this work, the modern ab initio valence bond (VB) method is employed to quantitatively investigate the torsional energy curves of hydrogen peroxide and hydrazine in terms of hyperconjugative stabilization, steric repulsion, and structural and electronic relaxations. It is found that if the hyperconjugation effect is completely quenched, the trans conformers will be favored, while the cis conformers are the only transition state pertaining to the torsional motion in the potential energy surfaces of H2O2 and N2H4. Although usually the steric effect includes the contributions from the electronic and geometric changes, our energy decomposition analysis shows that even the steric effect favors the skew conformers, while the electronic and geometric changes stabilize the trans conformers. Thus, we conclude that both the hyperconjugative and steric interactions lower the energy of skew conformers and eventually form low barriers from skew to trans conformers and high barriers from skew to cis conformers in both H2O2 and N2H4. Comparison between the VB and the natural bond orbital (NBO) results show similarities and discrepancies between the two methods.

Structure and stability of binary transition-metal clusters (NbCo)n (n < or = 5): a relativistic density-functional study.

Equilibrium geometries and electronic properties of binary transition-metal clusters, (NbCo)n (n < or = 5), have been investigated by means of the relativistic density-functional approach. The metal-metal bonding and stability aspects of these clusters have been analyzed on the basis of calculations. Present results show that these clusters exhibit rich structural varieties on the potential-energy surfaces. The most stable structures have a compact conformation in relatively high symmetry, in which the Nb atoms prefer to form an inner core and Co atoms are capped to the facets of the core. Such building features in clustering of the Nb/Co system are related to the order of bond strength: Nb-Nb>Nb-Co>Co-Co. As the binary cluster size increases, the Nb-Co bond may become stronger than the Nb-Nb bond in the inner niobium core, which results in a remarkable increment of the Nb-Nb bond length. Amongst these binary transition-metal clusters, the singlet (NbCo)4 in T(d) symmetry has a striking high stability due to the presence of the spherical aromaticity and electronic shell closure. The size dependence of the bond length and stability of the cluster has been explored.

Effects of chain length and Au spin-orbit coupling on 3(pi pi*) emission from bridging Cn2- units: theoretical characterization of spin-forbidden radiative transitions in metal-capped one-dimensional carbon chains [H3PAu(C[triple bond]C)nAuPH3].

Density functional theory and CASSCF calculations have been used to optimize the geometries of binuclear gold(I) complexes [H(3)PAu(C[triple bond]C)(n)AuPH(3)] (n=1-6) in their ground states and selected lowest energy (3)(pi pi*) excited states. Vertical excitation energies obtained by time-dependent density functional calculations for the spin-forbidden singlet-triplet transitions have exponential-decay size dependence. The predicted singlet-triplet splitting limit of [H(3)PAu(C[triple bond]C)(proportional/variant)AuPH(3)] is about 8317 cm(-1). Calculated singlet-triplet transition energies are in reasonable agreement with available experimental observations. The effect of the heavy atom Au spin-orbit coupling on the (3)(pi pi*) emission of these metal-capped one-dimensional carbon allotropes has been investigated by MRCI calculations. The contribution of the spin- and dipole-allowed singlet excited state to the spin-orbit-coupling wave function of the (3)(pi pi*) excited state makes the low-lying acetylenic triplet excited states become sufficiently allowed so as to appear in both electronic absorption and emission.

Diradical mechanisms for the cycloaddition reactions of 1,3-butadiene, benzene, thiophene, ethylene, and acetylene on a Si(111)-7x7 surface.

The cycloaddition chemistry of several representative unsaturated hydrocarbons (1,3-butadiene, benzene, ethylene, and acetylene) and a heterocyclic aromatic (thiophene) on a Si(111)-7x7 surface has been explored by means of density functional cluster model calculations. It is shown that (i) 1,3-butadiene, benzene, and thiophene can undergo both [4+2]-like and [2+2]-like cycloadditions onto a rest atom-adatom pair, with the former process being favored over the latter both thermodynamically and kinetically; (ii) ethylene and acetylene undergo [2+2] cycloaddition-like chemisorptions onto a rest atom-adatom pair; and (iii) all of these reactions adopt diradical mechanisms. This is in contrast to the [4+2] cycloaddition-like chemisorptions of conjugated dienes on a Si(100) surface and to the prototype [4+2] cycloadditions in organic chemistry, which were believed to adopt concerted reaction pathways. Of particular interest is the [4+2]-like cycloaddition of s-trans-1,3-butadiene, whose stereochemistry is retained during its chemisorption on the Si(111) surface.

Charge transfer in the electron donor-acceptor complex BH3NH3.

As a simple yet strongly binding electron donor-acceptor (EDA) complex, BH(3)NH(3) serves as a good example to study the electron pair donor-acceptor complexes. We employed both the ab initio valence bond (VB) and block-localized wave function (BLW) methods to explore the electron transfer from NH(3) to BH(3). Conventionally, EDA complexes have been described by two diabatic states: one neutral state and one ionic charge-transferred state. Ab initio VB self-consistent field (VBSCF) computations generate the energy profiles of the two diabatic states together with the adiabatic (ground) state. Our calculations evidently demonstrated that the electron transfer between NH(3) and BH(3) falls in the abnormal regime where the reorganization energy is less than the exoergicity of the reaction. The nature of the NH(3)-BH(3) interaction is probed by an energy decomposition scheme based on the BLW method. We found that the variation of the charge-transfer energy with the donor-acceptor distance is insensitive to the computation levels and basis sets, but the estimation of the amount of electron transferred heavily depends on the population analysis procedures. The recent resurgence of interest in the nature of the rotation barrier in ethane prompted us to analyze the conformational change of BH(3)NH(3), which is an isoelectronic system with ethane. We found that the preference of the staggered structure over the eclipsed structure of BH(3)NH(3) is dominated by the Pauli exchange repulsion.

A practical valence bond method: a configuration interaction method approach with perturbation theoretic facility.

The previously developed valence bond configuration interaction (VBCI) method (Wu, W.; Song, L.; Cao, Z.; Zhang, Q.; Shaik, S., J. Phys. Chem. A, 2002, 105, 2721) that borrows the general CI philosophy of the MO theory, is further extended in this article, and its methodological features are improved, resulting in three accurate and cost-effective procedures: (a) the effect of quadruplet excitation is incorporated using the Davidson correction, such that the new procedure reduces size consistency problems, with due improvement in the quality of the computational results. (b) A cost-effective procedure, named VBCI(D, S), is introduced. It includes doubly excited structures for active electrons and singly excited structures for inactive pairs. The computational results of VBCI(D, S) match those of VBCISD with much less computational effort than VBCISD. (c) Finally, a second-order perturbation theory is utilized as a means of configuration selection, and lead to considerable reduction of the computational cost, with little or no loss in accuracy. Applications of the new procedures to bond energies and barriers of chemical reactions are presented and discussed.