Siddhartha Maiti

Bio: Siddhartha Maiti is an academic researcher from Indian Institute of Technology Bombay. The author has contributed to research in topics: Catalysis & Chemistry. The author has an hindex of 9, co-authored 15 publications receiving 379 citations. Previous affiliations of Siddhartha Maiti include University of Massachusetts Dartmouth.

α-Synuclein aggregation nucleates through liquid-liquid phase separation.

Abstract: α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson's disease pathogenesis. However, the early events involved in this process remain unclear. Here, using the in vitro reconstitution and cellular model, we show that liquid-liquid phase separation of α-Syn precedes its aggregation. In particular, in vitro generated α-Syn liquid-like droplets eventually undergo a liquid-to-solid transition and form an amyloid hydrogel that contains oligomers and fibrillar species. Factors known to aggravate α-Syn aggregation, such as low pH, phosphomimetic substitution and familial Parkinson's disease mutations, also promote α-Syn liquid-liquid phase separation and its subsequent maturation. We further demonstrate α-Syn liquid-droplet formation in cells. These cellular α-Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. This work provides detailed insights into the phase-separation behaviour of natively unstructured α-Syn and its conversion to a disease-associated aggregated state, which is highly relevant in Parkinson's disease pathogenesis.

Rhodium catalyzed template-assisted distal para-C–H olefination

Abstract: Rhodium catalysis has been extensively used for ortho-C-H functionalization reactions, and successfully extended to meta-C-H functionalization. Its application to para-C-H activation remains an unmet challenge. Herein we disclose the first example of such a reaction, with the Rh-catalyzed para-C-H olefination of arenes. The use of a Si-linked cyanobiphenyl unit as a traceless directing group leads to highly para-selective arene-olefin couplings.

Palladium-Catalyzed Directed meta-Selective C−H Allylation of Arenes: Unactivated Internal Olefins as Allyl Surrogates

Abstract: Palladium(II)-catalyzed meta-selective C-H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ-donating and π-accepting ability of pyrimidine-based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E stereoselectivity were achieved with broad substrate scope, wide functional-group tolerance, and good to excellent yields. Late-stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed light on the mechanism and point to key steric control in the palladacycle, thus determining product selectivities.

Reaction-based turn-on fluorescent probes with magnetic responses for Fe2+ detection in live cells

Abstract: Iron is the most abundant nutritionally essential transition metal found in the human body. It plays important roles in various biological processes such as oxygen delivery, electron transport, enzymatic reactions and DNA synthesis and repair. However, iron can also catalyze the production of free radicals, which are linked to quite a few diseases such as cancer, neurodegenerative diseases, and cardiovascular diseases. Both iron deficiency and iron overload are related to various health problems. Thus, precisely monitoring iron ions (Fe2+ and Fe3+) in biological systems is important in understanding the detailed biological functions of iron and its trafficking pathways. However, effective tools for monitoring labile Fe2+ in biological systems have not yet been established. Reported herein are turn on, reaction-based coumarin and rhodamine-linked nitroxide probes (Cou-T and Rh-T) for selective detection of Fe2+ in solution and in living cells. Rh-T displayed a unique change in the EPR signal as well as enhancement of the fluorescence signal resulting from a specific redox reaction between the probe and Fe2+. The turn-on fluorescence response towards Fe2+ allows the subcellular imaging of endogenous Fe2+ as well as imaging under conditions of external iron supplementation or depletion, with a labile Fe2+ pool located in the mitochondria of human fibroblast primary cells. The detection and mechanism were verified by the magnetic properties of the probe via electron paramagnetic resonance (EPR) spectroscopy in solution and in cells.

Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide

Abstract: Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This perspective attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.

Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing.

Abstract: Biomolecular condensates are membraneless intracellular assemblies that often form via liquid-liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.

Achieving Site-Selectivity for C-H Activation Processes Based on Distance and Geometry: A Carpenter's Approach.

Abstract: The ability to differentiate between highly similar C-H bonds in a given molecule remains a fundamental challenge in organic chemistry. In particular, the lack of sufficient steric and electronic differences between C-H bonds located distal to functional groups has prevented the development of site-selective catalysts with broad scope. An emerging approach to circumvent this obstacle is to utilize the distance between a target C-H bond and a coordinating functional group, along with the geometry of the cyclic transition state in directed C-H activation, as core molecular recognition parameters to differentiate between multiple C-H bonds. In this Perspective, we discuss the advent and recent advances of this concept. We cover a wide range of transition-metal-catalyzed, template-directed remote C-H activation reactions of alcohols, carboxylic acids, sulfonates, phosphonates, and amines. Additionally, we review eminent examples which take advantage of non-covalent interactions to achieve regiocontrol. Continued advancement of this distance- and geometry-based differentiation approach for regioselective remote C-H functionalization reactions may lead to the ultimate realization of molecular editing: the freedom to modify organic molecules at any site, in any order.

Beyond aggregation: Pathological phase transitions in neurodegenerative disease.

Abstract: Over the past decade, phase transitions have emerged as a fundamental mechanism of cellular organization. In parallel, a wealth of evidence has accrued indicating that aberrations in phase transitions are early events in the pathogenesis of several neurodegenerative diseases. We review the key evidence of defects at multiple levels, from phase transition of individual proteins to the dynamic behavior of complex, multicomponent condensates in neurodegeneration. We also highlight two concepts, dynamical arrest and heterotypic buffering, that are key to understanding how pathological phase transitions relate to pleiotropic defects in cellular functions and the accrual of proteinaceous deposits at end-stage disease. These insights not only illuminate disease etiology but also are likely to guide the development of therapeutic interventions to restore homeostasis.