Department of Chemistry

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IIT Jodhpur

Molecular design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody-drug conjugates are described. Among the new discoveries reported is the identification of new potent analogues within the tubulysin family that carry a C11 alkyl ether substituent, rather than the usual ester structural motif at that position, a fact that endows the former with higher plasma stability than that of the latter. Also described herein are X-ray crystallographic analysis studies of two tubulin-tubulysin complexes formed within the α/β interface between two tubulin heterodimers and two highly potent tubulysin analogues, one of which exhibited a different binding mode to the one previously reported for tubulysin M. The X-ray crystallographic analysis-derived new insights into the binding modes of these tubulysin analogues explain their potencies and provide inspiration for further design, synthesis, and biological investigations within this class of antitumor agents. A number of these analogues were conjugated as payloads with appropriate linkers at different sites allowing their attachment onto targeting antibodies for cancer therapies. A number of such antibody-drug conjugates were constructed and tested, both in vivo and in vitro, leading to the identification of at least one promising ADC (Herceptin-LD3), warranting further investigations. © 2021 American Chemical Society.

World University root node

Journal of Organic Chemistry

Design, Synthesis, and Biological Evaluation of Tubulysin Analogues, Linker-Drugs, and Antibody-Drug Conjugates, Insights into Structure-Activity Relationships, and Tubulysin-Tubulin Binding Derived from X-ray Crystallographic Analysis

Synthetic methods enabling late-stage modification of heterocycles hold tremendous importance in the pharmaceutical and agrochemical industry and drug discovery. Accordingly, efficient, functional group tolerant and selective late-stage alkylation of valuable molecular entities is of enormous significance and well-acknowledged in medicinal chemistry. Radical alkylation of heteroarenes employing carboxylic acids as the alkyl radical precursor represents one of the most direct ways of C−H functionalizations of heterocycles. Recently, the field has undergone a revolutionary development especially with regard to the generation of alkyl radicals under much milder conditions. In this regard N-(acyloxy)phthalimides (NHPI esters) have emerged as a suitable precursor of a diverse set of alkyl radicals allowing formal C−H alkylation of not only N-heteroarenes but a diverse set of non-aromatic heterocycles under visible light photocatalysis or electrochemical conditions. This review delineates all these discoveries and provides readers a comprehensive overview of this rapidly expanding field. © 2021 Wiley-VCH GmbH

Chemistry - An Asian Journal

Late-Stage Alkylation of Heterocycles Using N-(Acyloxy)phthalimides

Understanding the influence of dehydration on the membrane structure is crucial to control membrane functionality related to domain formation and cell fusion under anhydrobiosis conditions. To this end, we perform all-atom molecular dynamic simulations of 1,2-dimyristoyl-sn-glycero-3-phosphocholine dimyristoylphosphatidylcholine lipid membranes at different hydration levels at 308 K. As dehydration increases, the lipid area per head group decreases with an increase in bilayer thickness and lipid order parameters indicating bilayer ordering. Concurrently, translational and rotational dynamics of interfacial water (IW) molecules near membranes slow down. On the onset of bilayer ordering, the IW molecules exhibit prominent features of dynamical heterogeneity evident from non-Gaussian parameters and one-dimensional van Hove correlation functions. At a fully hydrated state, diffusion constants (D) of the IW follow a scaling relation, D∼τα-1, where the α relaxation time (τα) is obtained from self-intermediate scattering functions. However, upon dehydration, the relation breaks and the D of the IW follows a power law behavior as D∼τα-0.57, showing the signature of glass dynamics. τα and hydrogen bond lifetime calculated from intermittent hydrogen bond auto-correlation functions undergo a similar crossover in association with bilayer ordering on dehydration. The bilayer ordering is accompanied with an increase in fraction of caged lipids spanned over the bilayer surface and a decrease in fraction of mobile lipids due to the non-diffusive dynamics. Our analyses reveal that the microscopic mechanism of lipid ordering by dehydration is governed by dynamical heterogeneity. The fundamental understanding from this study can be applied to complex bio-membranes to trap functionally relevant gel-like domains at room temperature. © 2021 Author(s).

Fulltext

Journal of Chemical Physics

Dehydration induced dynamical heterogeneity and ordering mechanism of lipid bilayers

Abstract: The structural basis for the stability of the trimeric form of the light harvesting complex (LHCII), a pigmented protein from green plants pivotal for photosynthesis, remains elusive till date. The protein embedded in a dipalmitoylphosphatidylcholine (DPPC) lipid membrane is investigated using all-atom molecular dynamics simulations to find out the interactions responsible for the structural integrity of the trimer and its relation to antenna function. Central association of chlorophyll a (CLA) molecules near the LHCII chains is attributed to a conserved coordination between the Mg of CLA and the oxygen of a specific residue of the first helix of a chain. The residue forms a salt-bridge with the fourth helix of the same chain of the trimer, not of the monomer. In an earlier experiment, three residues (WYR) at each chain of the trimer have been found indispensable for the trimerization and referred to as trimerization motif. We find that the residues of the trimerization motif are connected to the lipids or pigments by a chain of interactions rather than a direct contact. Synergistic effects of sequentially located hydrogen bonds and salt-bridges within monomers of the trimer keep the trimer conformation stable in association with the pigments or the lipids. These interactions are exclusively present in the pigmented trimer and not present in the monomer or in the unpigmented trimer. Thus, our results provide a molecular basis for the inherent stability of the LHCII trimer in a lipid membrane and explain many pre-existing experimental data. Graphic Abstract: [Figure not available: see fulltext.] © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Journal of Membrane Biology

Interactions Determining the Structural Integrity of the Trimer of Plant Light Harvesting Complex in Lipid Membranes

The role of second-order saddle in the isomerization dynamics was investigated by considering the E-Z isomerization of guanidine. The potential energy profile for the reaction was mapped using the ab initio wavefunction method. The isomerization path involved a torsional motion about the imine (C-N) bond in a clockwise or an anticlockwise fashion resulting in two degenerate transition states corresponding to a barrier of 23.67 kcal/mol.An alternative energetically favorable path (~1 kcal/mol higher than the transition states) by an in-plane motion of the imine (N-H) bond via a second-order saddle point on the potential energy surface was also obtained. The dynamics of the isomerization was investigated by ab initio classical trajectory simulations. The trajectories reveal that isomerization happens via the transition states as well as the second-order saddle. The dynamics was found to be nonstatistical with trajectories exhibiting recrossing and the higher energy second-order saddle pathway preferred over the traditional transition state pathway. Wavelet based time-frequency analysis of internal coordinates indicate regular dynamics and existence of long-lived quasi-periodic trajectories in the phase space. © 2021, Pleiades Publishing, Ltd.

Regular and Chaotic Dynamics

Second-order Saddle Dynamics in Isomerization Reaction

Hydroxido-bridged dinuclear monoorganostannoxane [(RSnIV)2(μ-OH)(μ-OMe)Cl4]·CH3OH (R = 2-phenylazophenyl) (1) was obtained by the reaction of RSnCl3 (R = 2-phenylazophenyl) with sodium hydroxide in a stoichiometric ratio of acetone/methanol (1:1) at room temperature. Compound 1 crystallizes in the monoclinic space group Cc. The partial hydrolysis of RSnCl3 is accompanied by the substitution of two chlorides by one hydroxido and one methoxy ligand. The molecular structure of 1 contains two tin centers in distorted octahedral geometry which are bridged by hydroxido and methoxy ligands. In addition, single-crystal X-ray diffraction analysis of 1 revealed the formation of 1-D and 2-D supramolecular architectures because of the intermolecular hydrogen bonding and CH···πinteractions. Density functional theory studies suggested that the major transitions occurring in 1 involves ligand to ligand transitions. The reduced species calculations on compound 1 results are compatible to show the negative differential resistance (NDR) effect in this molecule. The I-V characteristic studies of a device made using compound 1 revealed that it exhibits very interesting NDR behavior in the region of 1.5-2.5 V. ©

Department of Physics

ACS Applied Electronic Materials

Dinuclear Monoorganostannoxane [(RSnIV)2(μ-OH)(μ-OCH3)Cl4]·CH3OH (R= 2-(Phenylazo)phenyl) Assembled Using Intramolecular Coordination Approach: Design of Organostannoxane-Based NDR Device

A transition-metal-free one-pot three-component annulation between diaryliodonium triflates, cyclic and acyclic aliphatic amines, and carbon disulfide providing a convenient and efficient access to biologically relevant S-aryl dithiocarbamates is developed. The reaction does not require metal, base, or any other additive and operates under mild and ambient conditions. This methodology is robust, scalable, and exhibits a broad substrate scope. The in silico analysis revealed that the majority of the compounds have a drug-likeness and good ADMET characteristics.

ORGANIC LETTERS

Multicomponent Synthesis of Biologically Relevant S-Aryl Dithiocarbamates Using Diaryliodonium Salts

Since the last decades, solar energy has been used worldwide to overcome foreign dependency on crude oil and to control the pollution due to a limited source of non-renewable energy. Evacuated tube solar collectors are the most suitable solar technology for producing useful heat in both low and medium temperature levels. Evacuated tube solar collector is capable of working in hot, mild, cloudy or cold climates where flat plate collector is not an option. The objective of this review paper is the detailed investigation of evacuated tube solar collectors having heat pipe and direct flow are reviewed. All the design parameters which influence the collector performance are investigated and discussed in this work. More specifically, the tracking system, the collector design, the mass flow rate, the optical design and the kind of the working fluid are the main studied parameters. Moreover, this work focuses on the latest developments and advances, providing a review of experimental and numerical studies reported. Lastly, this work presents the future ideas that can be carried out to improve the performance of evacuated tube solar collectors.

JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY

An up-to-date review on evacuated tube solar collectors

Using the deprotonated forms of the tetradentate phenol amine ligands 2-((((1-methylbenzimidazol-2-yl)methyl)(pyridin-2-ylmethyl)amino)methyl)phenol (HL1) and 2-(((pyridin-2-ylmethyl)(quinolin-2-ylmethyl)amino)methyl)phenol (HL2), dinuclear copper(ii) complexes were synthesized. These ligands yielded two binuclear complexes with the composition [Cu2(Ln)2](ClO4)2 [n = 1, (1) and n = 2, (2)] and two mononuclear complexes with the compositions [Cu(HL1)(CH3CN)](ClO4)2 (3) and [Cu(HL2) (CH3CN)(OClO3)](ClO4) (4), which have been characterized using X-ray crystallography, UV-Vis, and magnetic susceptibility measurements. The magnetic susceptibility studies of 1 and 2 indicate moderate antiferromagnetic coupling between the CuII ions through the μ-phenoxo bridges [J = -38(2) and -145(1) cm-1, respectively], which is described by the Bleaney-Bowers dinuclear model. In contrast, 3 and 4 are devoid of any significant magnetic interactions between the mononuclear units. 3 and 4 show axial spectra typical of the d9 (dx2-y2 as the ground state) configuration. The dimer complexes 1 and 2 can be converted into the corresponding monomeric Cu(ii) complexes 3 and 4via adding two equivalents of an acid, such as perchloric acid (HClO4), to a CH3CN solution of the dimer. The dimeric core can be regenerated via adding an equivalent of a base, such as triethylamine (Et3N). Time-dependent density functional theory (TD-DFT) calculations using the M06 functional were performed in order to rationalize the electronic structures of the complexes and to shed light on the origin of the observed electronic transitions. Additionally, DFT/B3LYP calculations helped us to unambiguously state the sign and magnitude of the magnetic coupling constants along with an approximation of the spin density distribution. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

New Journal of Chemistry

The reversible inter-conversion of copper(ii) dimers bearing phenolate-based ligands in their monomers: theoretical and experimental viewpoints

A new octanuclear monoorganotin copper sulfide cage [(RSnCu)4(μ3-S)8]·2CHCl3 (1) (R = 2-phenylazophenyl) has been synthesized using the N→Sn intramolecular coordination approach. Complex 1 was obtained using the one pot reaction of monoorganotin trichloride, CuCl2 and Na2S·9H2O in Acetone/Methanol (1:1) solution. Complex 1 crystallizes in tetragonal P42/n space group. Formation of 1 is accompanied by the substitution of all the chlorides by sulfide ligand. The molecular structure of 1 contains four tin centers and four copper centers in distorted trigonal bipyramidal and distorted trigonal planar geometry respectively. Both Sn and Copper centers are further bridged by µ3-sulfide ligands. Closer inspection of solid state structure of 1 revealed the formation of 1-D and 2-D supramolecular architecture due to the various intermolecular interaction such as hydrogen bonding and CH–π interactions. Density functional theory (DFT) analysis of complex 1 has been performed to understand the orbital picture. The NBO analysis of complex 1 reveals three bonding interaction and two donor-acceptor interactions for tin (Sn) and three donor-acceptor interactions for copper (Cu). The AIM studies further demonstrate the clear picture of the various interactions present in the complex 1 using topological analysis scheme. These interactions are found to be ionic with partial/slight covalent characters. © 2021

Journal of Molecular Structure

Octanuclear Organotin Copper Sulfide Cage [(RSnCu)4(μ3-S)8]·2CHCl3 (R = 2-phenylazophenyl) Assembled using Intramolecular Coordination Approach: Synthesis, Structure and DFT-NBO-AIM Analysis