In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin)

Our screen for tubulin-binding small molecules that do not depolymerize bulk cellular microtubules, but based upon structural features of well known microtubule-depolymerizing colchicine and podophyllotoxin, revealed tubulin binding anti-cancer property of noscapine (Ye et al. in Proc Natl Acad Sci USA 95:2280–2286, 1998). Guided by molecular modelling calculations and structure–activity relationships we conjugated at C9 of noscapine, a folate group—a ligand for cellular folate receptor alpha (FRα). FRα is over-expressed on some solid tumours such as ovarian epithelial cancers. Molecular docking experiments predicted that a folate conjugated noscapine (Targetin) accommodated well inside the binding cavity (docking score −11.295 kcal/mol) at the interface between α- and β-tubulin. The bulky folate moiety of Targetin is extended toward lumen of microtubules. The binding free energy (ΔG _bind) computed based on molecular mechanics energy minimization was −221.01 kcal/mol that revealed favourable interaction of Targetin with the receptor. Chemical synthesis, tubulin-binding experiments, and anti-cancer activity in vitro corroborate fully well with the molecular modelling experiments. Targetin binds tubulin with a dissociation constant (K _d value) of 149 ± 3.0 μM and decreases the transition frequencies between growth and shortening phases of microtubule assembly dynamics at concentrations that do not alter the total polymer mass. Cancer cells in general were more sensitive to Targetin compared with the founding compound noscapine (IC₅₀ in the range of 15–40 μM). Quite strikingly, ovarian cancer cells (SKOV3 and A2780), known to overexpress FRα, were much more sensitive to targetin (IC₅₀ in the range of 0.3–1.5 μM).     

Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives

Background  

Nef is an HIV-1 accessory protein essential for viral replication and AIDS progression. Nef interacts with a multitude of host cell signaling partners, including members of the Src kinase family. Nef preferentially activates Hck, a Src-family kinase (SFK) strongly expressed in macrophages and other HIV target cells, by binding to its regulatory SH3 domain. Recently, we identified a series of kinase inhibitors that preferentially inhibit Hck in the presence of Nef. These compounds also block Nef-dependent HIV replication, validating the Nef-SFK signaling pathway as an antiretroviral drug target. Our findings also suggested that by binding to the Hck SH3 domain, Nef indirectly affects the conformation of the kinase active site to favor inhibitor association.     

Maximally Entangled States of a Two-Qubit System

Entanglement has been explored as one of the key resources required for quantum computation, the functional dependence of the entanglement measures on spin correlation functions has been established, correspondence between evolution of maximally entangled states (MES) of two-qubit system and representation of SU(2) group has been worked out and the evolution of MES under a rotating magnetic field has been investigated. Necessary and sufficient conditions for the general two-qubit state to be maximally entangled state (MES) have been obtained and a new set of MES constituting a very powerful and reliable eigen basis (different from magic bases) of two-qubit systems has been constructed. In terms of the MES constituting this basis, Bell’s States have been generated and all the qubits of two-qubit system have been obtained. It has shown that a MES corresponds to a point in the SO(3) sphere and an evolution of MES corresponds to a trajectory connecting two points on this sphere. Analysing the evolution of MES under a rotating magnetic field, it has been demonstrated that a rotating magnetic field is equivalent to a three dimensional rotation in real space leading to the evolution of a MES.     

Localized insulator-conductor transformation of graphene oxide thin films via focused laser beam irradiation

By scanning a focused laser beam over graphene oxide (GO) film deposited on SiO₂/Si substrates, conductive strips as small as 1 μm can be patterned directly either as a channel in the insulating matrix, or as a stand-alone micro belt. The conductivity was increased by at least two orders of magnitude with the mobility estimated in the range of 1–10 cm²/V s. Raman mapping and X-ray photoelectron spectroscopy studies demonstrated the reduction of GO in the laser-irradiated area. The conductance of the patterned channel was independent of the change in oxide-electrode contact resistance of the graphene, and increased linearly with increasing channel width. Increasing irradiation power by repeated scanning initially increased the conductivity of the irradiated area and saturated at a conductivity of ∼36 S/cm. Partial oxidative burning combined with photothermal reduction was identified as the underlying mechanism for the enhancement of the conductivity after laser irradiation on the GO film. Oxidative burning can be controlled by varying the film thickness and laser power.     

On the applicability of low-dimensional models for convective flow reversals at extreme Prandtl numbers

Constructing simpler models, either stochastic or deterministic, for exploring the phenomenon of flow reversals in fluid systems is in vogue across disciplines. Using direct numerical simulations and nonlinear time series analysis, we illustrate that the basic nature of flow reversals in convecting fluids can depend on the dimensionless parameters describing the system. Specifically, we find evidence of low-dimensional behavior in flow reversals occurring at zero Prandtl number, whereas we fail to find such signatures for reversals at infinite Prandtl number. Thus, even in a single system, as one varies the system parameters, one can encounter reversals that are fundamentally different in nature. Consequently, we conclude that a single general low-dimensional deterministic model cannot faithfully characterize flow reversals for every set of parameter values.     

Performance characteristics of positive and negative delayed feedback on chaotic dynamics of directly modulated InGaAsP semiconductor lasers

The chaotic dynamics of directly modulated semiconductor lasers with delayed optoelectronic feedback is studied numerically. The effects of positive and negative delayed optoelectronic feedback in producing chaotic outputs from such lasers with nonlinear gain reduction in its optimum value range is investigated using bifurcation diagrams. The results are confirmed by calculating the Lyapunov exponents. A negative delayed optoelectronic feedback configuration is found to be more effective in inducing chaotic dynamics to such systems with nonlinear gain reduction factor in the practical value range.      

A Review of Recent Progress in Solid State Fabrication of Composites and Functionally Graded Systems Via Friction Stir Processing

Friction stir processing (FSP) is a rapidly emerging newer solid-state technique for composite fabrication. It involves surface modification which in turn enables successful adaptation of surface properties through plastic deformations in solid state. During initial years of FSP inception, it was primarily employed in development of metal matrix composites of light metal alloys like aluminum. However, recently, it has gained an alluring role in fabrication of composites of various nonferrous and ferrous metal alloys as well as of polymers. In addition to composite fabrication, FSP has evolved as a revolutionary technique in developing functionally graded systems/surfaces (FGS) of metal matrix. This article covers all aspects of FSP in which reinforcement particles are embedded in the base matrix to develop composites and FGS. It presents a critical review on domains of recent developments, effects of different types of reinforcement particles and properties enhancement of composites, and FGS fabrication. In addition to this, various issues, challenges, and future work that demand attention are systematically addressed.     

Alkylchlorotins grafted to cross-linked polystyrene beads by a -(CH2)n- spacer (n=4, 6, 11): selective, clean and recyclable catalysts for transesterification reactions

Insoluble polystyrene grafted compounds of the type (P-H)(1-t){P-(CH2)n SnBu(p)Cl(3-p)}(t), (P-H)(1-t){P-(CH2)n SnBuO}(t) and (P-H)(1-t)[{P-(CH2)n SnBuCl}2O](t/2), in which (P-H) is a cross-linked polystyrene; n=4, 6, and 11; p=0 and 1; and t the degree of functionalisation, were synthesised from Amberlite XE-305, a polystyrene cross-linked with divinylbenzene. The compounds were characterised by using elemental analysis, and IR, Raman, solid-state 117Sn NMR, and 1H and 119Sn high-resolution MAS NMR spectroscopy. The influence of the spacer length and the tin functionality on the catalytic activity of these compounds, as well as their recycling ability, was assessed in the transesterification reaction of ethyl acetate with various alcohols. These studies showed significant differences in the activity of the catalysts interpreted in terms of changes in the mobility of the catalytic centres. Some of the supported catalysts could be recycled at least seven times without noticeable loss of activity. The residual tin content in the reaction products was found to be as low as 3 ppm.     

A new pentacyclic pyrylium fluorescent probe that responds to pH imbalance during apoptosis

Efficient fluorophores with easy synthetic routes and fast responses are of great importance in clinical diagnostics. Herein, we report a new, rigid pentacyclic pyrylium fluorophore, PS-OMe, synthesised in a single step by a modified Vilsmeier–Haack reaction. Insights into the reaction mechanism facilitated a new reaction protocol for the efficient synthesis of PS-OMe which upon demethylation resulted in a “turn-on” pH sensor, PS-OH. This new fluorescent probe has been successfully used to monitor intracellular acidification at physiological pH. From the fluorescence image analysis, we were able to quantify the intracellular dynamic pH change during apoptosis. This new pH probe is a potential chemical tool for screening, drug discovery and dose determination in cancer therapy.

A modified Vilsmeier–Haack reaction resulted in the synthesis of a pyrylium based turn-on fluorescent pH probe. The probe can monitor minute acidification and dynamic pH variation in cells during apoptosis with therapeutic chemo drugs.     

Applications of Singh-Rajput Mes in Recall Operations of Quantum Associative Memory for a Two- Qubit System

Recall operations of quantum associative memory (QuAM) have been conducted separately through evolutionary as well as non-evolutionary processes in terms of unitary and non- unitary operators respectively by separately choosing our recently derived maximally entangled states (Singh-Rajput MES) and Bell’s MES as memory states for various queries and it has been shown that in each case the choices of Singh-Rajput MES as valid memory states are much more suitable than those of Bell’s MES. it has been demonstrated that in both the types of recall processes the first and the fourth states of Singh-Rajput MES are most suitable choices as memory states for the queries ‘11’ and ‘00’ respectively while none of the Bell’s MES is a suitable choice as valid memory state in these recall processes. It has been demonstrated that all the four states of Singh-Rajput MES are suitable choice as valid memory states for the queries ‘1?’, ‘?1’, ‘?0’ and ‘0?’ while none of the Bell’s MES is suitable choice as the valid memory state for these queries also.