Subhankar Panda

Membrane Interaction and Protein Kinase C‑C1 Domain Binding Properties of 4‑Hydroxy-3-(hydroxymethyl) Phenyl Ester Analogues

Protein kinase C (PKC)-C1 domain targeted regulator development is considered as a potential therapeutic strategy for the treatment of cancer and immunological and other diseases. Efforts are underway to synthesize small molecules to achieve higher specificity for the C1-domain than the natural activator, diacylglycerols (DAGs). In this regard, we conveniently synthesized 4-hydroxy-3-(hydroxymethyl) phenyl ester analogues and measured in vitro C1-domain binding properties. We also investigated different physicochemical properties of the synthesized molecules, including aggregation behavior in aqueous solution and interaction with lipid bilayers, and others with an aim for better understanding of their C1-domain binding properties. The results showed that the membrane-active compounds aggregate in aqueous solution at a reasonably lower concentration and strongly interact with the lipid bilayer. The hydrophilic part of the compounds localize at the bilayer/water interface and accessible for C1-domain binding. Biophysical studies revealed that the hydroxyl, hydroxymethyl, and carbonyl groups and acyl chain length are important for their interaction with the C1-domain. The potent compound showed more than 10-fold stronger binding affinity for the C1-domains than DAG under similar experimental conditions. Therefore, our findings reveal that these ester analogues represent an attractive group of C1-domain ligands that can be further structurally modified to improve their binding and activity.

Transition Metal, Azide, and Oxidant-Free Homo- and Heterocoupling of Ambiphilic Tosylhydrazones to the Regioselective Triazoles and Pyrazoles

With N-tosylhydrazone as an ambiphilic reagent, an unprecedented cyclization reaction of two identical or different tosylhydrazones has been developed to access various 4,5-disubstituted-2H-triazoles under transition metal, azide, and oxidant-free conditions. A mechanistic rationalization study led to the identification of several electronically diverse unsaturated systems for regioselective synthesis of 1- and 2-substituted 1,2,3-triazoles and pyrazoles.

Azidophosphonate Chemistry as a Route for a Novel Class of Vesicle‐Forming Phosphonolipids

Membrane forming synthetic lipids constitutes a new class of biomaterials with impressive applications in the field of biological and pharmaceutical sciences. Interestingly, alteration(s) in the headgroup region of the lipids offer a wide chemical space to investigate their specific properties. In this regard, we have utilized β-azidophosphonate chemistry to gain access to a novel class of triazole-phosphonate (TP) amphiphiles with fascinating physicochemical properties of lipids. TP lipids form stable vesicles that exhibit negative surface potential across a broad pH range. These anionic lipids have high phase-transition temperatures, phospholipase resistance, slow vesicle leakage profiles, and doxorubicin delivery efficacy. We hypothesize that these readily synthesizable phosphonolipids could find several applications as phospholipid substituents.

Ring-Opening of Indoles: An Unconventional Route for the Transformation of Indoles to 1H-Pyrazoles Using Lewis Acid

An unusual transformation of indoles to pyrazoles via an aromatic ring-opening strategy has been developed. The salient feature of this strategy involves the C2-N1 bond opening and concomitant cyclization reaction of the C2═C3 bond of the indole moiety with the tosylhydrazone, which proceeds under transition-metal and ligand free conditions. This ring-opening functionalization of indoles provides a wide scope of differently substituted pyrazoles.

Diphenylethylenediamine-Based Potent Anionophores: Transmembrane Chloride Ion Transport and Apoptosis Inducing Activities

Synthetic anion transporters have been recognized as one of the potential therapeutic agents for the treatment of diseases including cystic fibrosis, myotonia, and epilepsy that originate due to the malfunctioning of natural Cl- ion transport systems. Recent studies showed that the synthetic Cl- ion transporters can also disrupt cellular ion-homeostasis and induce apoptosis in cancer cell lines, leading to a revived attention for synthetic Cl- ion transporters. Herein, we report the development of conformationally controlled 1,2-diphenylethylenediamine-based bis(thiourea) derivatives as a new class of selective Cl- ion carrier. The strong Cl- ion binding properties ( Kd = 3.87-6.66 mM) of the bis(thiourea) derivatives of diamine-based compounds correlate well with their transmembrane anion transport activities (EC50 = 2.09-4.15 nM). The transport of Cl- ions via Cl-/NO3- antiport mechanism was confirmed for the most active molecule. Perturbation of Cl- ion homeostasis by this anion carrier induces cell death by promoting the caspase-mediated intrinsic pathway of apoptosis.