Discovery of novel benzamide derivatives bearing benzamidophenyl and phenylacetamidophenyl scaffolds as potential antitumor agents via targeting PARP-1.

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a crucial role in DNA damage repair and has been identified as a promising therapeutic target in cancer therapy. As a continuation of our efforts on the development of novel PARP-1 inhibitors with potent anticancer activity, a series of benzamide derivatives containing the benzamidophenyl and phenylacetamidophenyl scaffolds were designed and synthesized based on the structure optimization of our previously reported compound IX. All target compounds were screened for their in vitro antiproliferative activities against human colorectal cancer cells (HCT116, DLD-1 and SW480) and human normal colonic epithelial cells (NCM460). Among them, compound 13f exhibited the most potent anticancer activity against HCT116 cells and DLD-1 cells with IC50 = 0.30 µM and 2.83 µM, respectively. Moreover, 13f displayed significant selectivity in inhibiting HCT116 cancer cells over the normal NCM460 cells. Furthermore, 13f exhibited excellent PARP-1 inhibitory effect with IC50 = 0.25 nM. Besides, 13f was found to effectively inhibit colony formation and migration of HCT116 cells. Studies on the mechanisms revealed that 13f could arrest cell cycle at G2/M phase, accumulate DNA double-strand breaks, reduce mitochondrial membrane potential and ultimately induce apoptosis in HCT116 cells. In addition, molecular docking study indicated that 13f could combine firmly with the catalytic pocket of PARP-1 through multiple hydrogen bond interactions. Collectively, these findings demonstrated that 13f could serve as a promising anticancer candidate and deserves further investigation.

Design, synthesis, biological evaluation and molecular docking study of novel urea-based benzamide derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) is one of the key members of DNA repair enzymes that is responsible for the repair of DNA single-strand breaks. Inhibition of PARP-1 has been demonstrated to be a promising strategy to selectively kill tumor cells by targeting DNA repair pathway. Herein, a series of novel urea-based benzamide derivatives were designed and synthesized based on the structure-based drug design strategy. The anticancer activities against five human cancer cell lines including HCT116, MDA-MB-231, HeLa, A579 and A375 were evaluated and the preliminary structure-activity relationships were summarized. Among them, compounds 23f and 27f exhibited potent antiproliferative effects against HCT116 cells with IC50 values of 7.87 µM and 8.93 µM, respectively. Moreover, both compounds displayed excellent PARP-1 inhibitory activities with IC50 values of 5.17 nM and 6.06 nM, respectively. Mechanistic investigations showed that 23f and 27f could effectively inhibit colony formation and cell migration of HCT116 cells. Furthermore, 23f and 27f could cause cell cycle arrest at G2/M phase, and induce apoptosis by upregulating the expression of Bax and cleaved Caspase-3 and downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. In addition, molecular docking studies provided the rational binding modes of these compounds in complex with PARP-1. Collectively, these results suggested that 23f and 27f could serve as promising drug candidates for further investigation.

Suffrutines A and B Inhibit the Expression of Inflammatory Mediators in LPS-Induced RAW264.7 Cells by Suppressing the NF-κB Signaling Pathway.

Flueggea suffruticosa is a traditional Chinese medicine that has been commonly used for the treatment of inflammatory ailments, including rheumatism and lumbago. Suffrutines A and suffrutines B are a pair of novel E,E and Z,E isomeric indolizidine alkaloids isolated from the roots of F. suffruticosa. However, their anti-inflammatory activity has not been reported thus far. The aim of this study was to investigate the inhibitory effect of inflammatory mediators and possible mechanisms of suffrutines A and B in lipopolysaccharide-induced RAW264.7 cells. Results showed that suffrutines A and B could remarkably inhibit the production of nitric oxide, prostaglandin E2, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 in lipopolysaccharide-induced RAW264.7 cells. Further evaluation demonstrated that compared with suffrutines A, suffrutines B could more significantly inhibit the phosphorylation of IKKα/ß, the degradation of IκBα, and the nuclear translocation of the p65 and p52 subunits in the canonical and non-canonical nuclear factor-κB pathways. Therefore, suffrutines B exhibited more potent inhibitory activity on inflammatory mediators than suffrutines A.

Flat-band ferromagnetism of SU(N) Hubbard model on Tasaki lattices.

We investigate the para-ferro magnetic transition of the repulsive SU(N) Hubbard model on a type of one- and two-dimensional decorated cubic lattices, referred as Tasaki lattices, which feature massive single-particle ground state degeneracy. Under certain restrictions for constructing localized many-particle ground states of flat-band ferromagnetism, the quantum model of strongly correlated electrons is mapped to a classical statistical geometric site-percolation problem, where the nontrivial weights of different configurations must be considered. We prove rigorously the existence of para-ferro transition for the SU(N) Hubbard model on one-dimensional Tasaki lattice and determine the critical density by the transfer-matrix method. In two dimensions, we numerically investigate the phase transition of SU(3), SU(4) and SU(10) Hubbard models by Metropolis Monte Carlo simulation. We find that the critical density exceeds that of standard percolation, and increases with spin degrees of freedom, implying that the effective repulsive interaction becomes stronger for larger N. We further rigorously prove the existence of flat-band ferromagnetism of the SU(N) Hubbard model when the number of particles equals to the degeneracy of the lowest band in the single-particle energy spectrum.

Orbital angular momentum and spectral flow in two-dimensional chiral superfluids.

We study the orbital angular momentum (OAM) L_{z} in two-dimensional chiral (p_{x}+ip_{y})^{ν}-wave superfluids (SFs) of N fermions on a disk at zero temperature, in terms of spectral asymmetry and spectral flow. It is shown that L_{z}=νN/2 for any integer ν, in the Bose-Einstein condensation regime. In contrast, in the BCS limit, while the OAM is L_{z}=N/2 for the p+ip-wave SF, for chiral SFs with ν≥2, the OAM is remarkably suppressed as L_{z}=N×O(Δ_{0}/ϵ_{F})≪N, where Δ_{0} is the gap amplitude and ϵ_{F} is the Fermi energy. We demonstrate that the difference between the p+ip-wave SF and the other chiral SFs in the BCS regimes originates from the nature of edge modes and related depairing effects.

Ground-state energies of spinless free fermions and hard-core bosons.

We compare the ground-state energies of bosons and fermions with the same form of the Hamiltonian. If both are noninteracting, the ground-state energy of bosons is always lower, owing to Bose-Einstein condensation. However, the comparison is nontrivial when bosons do interact. We first prove that, when the hopping is unfrustrated (all the hopping amplitudes are non-negative), hard-core bosons still must have a lower ground-state energy than fermions. If the hopping is frustrated, bosons can have a higher ground-state energy than fermions. We prove rigorously that this inversion indeed occurs in several examples.