Natural Product-Inspired Small Molecules for Cancer and Neurodegeneration: From Synthesis to Therapeutic Mechanisms

Natural products research occupies a central role in modern medicinal chemistry and chemical biology. Over recent decades, compounds originating from natural sources and their semi synthetic derivatives have been instrumental in drug discovery, particularly in oncology and neurodegenerative diseases. Despite remarkable advances, therapeutic development based on natural product scaffolds continues to face challenges, including limited natural abundance, structural complexity, suboptimal pharmacokinetic properties, blood–brain barrier permeability, and incomplete understanding of molecular mechanisms of action. Recent studies have highlighted the potential of stereochemically defined analogs and rationally modified scaffolds to overcome these limitations, leading to improved bioavailability, target selectivity, and therapeutic efficacy. Synthetic and semi synthetic approaches serve as essential tools for unlocking and optimizing the biological activities of natural product scaffolds. Advances in medicinal chemistry, chemical biology, natural product isolation, biosynthesis and biosynthetic pathway engineering, computational modeling, artificial intelligence (AI) assisted drug design, and bioactivity guided discovery have expanded the accessible chemical space surrounding natural products, facilitating the identification of novel pharmacophores, molecular targets, and therapeutic mechanisms. Continued exploration of natural product inspired small molecules remains critical for developing innovative therapeutic strategies against complex multifactorial disorders, including cancer and neurodegenerative diseases.This Research Topic aims to advance the characterization and optimization of the biological activities of small molecules inspired by natural products, bridging bioactivity guided chemistry and molecular therapeutics. All submissions must maintain a clear and traceable link to a natural product scaffold, precursor, or biosynthetic origin; purely synthetic candidates without demonstrable natural product ancestry fall outside the scope of this Research Topic. It seeks to elucidate how chemical modifications influence biological activity, explore cellular and molecular mechanisms of enzymatic and signaling pathway modulation, and uncover precise molecular targets driving pharmacological efficacy in cancer and neurodegenerative diseases. Particular emphasis will be placed on studies dissecting structure–activity relationships (SAR), mechanisms of enzyme inhibition, epigenetic regulation, neuroinflammation, apoptosis, oxidative stress responses, mitochondrial dysfunction, autophagy, ferroptosis, and other disease relevant pathways. We also welcome investigations identifying molecular interactions underpinning the therapeutic potential of polyphenolic, alkaloidal, terpenoid, peptide derived, and other natural product inspired analogs.The scope of this Research Topic encompasses experimental, computational, and theoretical investigations on the discovery, isolation, biosynthesis, characterization, synthesis, optimization, and biological evaluation of natural product inspired compounds. Studies may focus on methodological innovation, mechanistic discovery, target identification and validation, molecular pharmacology, pharmacokinetic profiling, or translational development, provided they demonstrate clear therapeutic relevance to cancer and neurodegenerative disorders and a direct connection to a natural product source or scaffold.To gather further insights into this interdisciplinary field, we welcome articles addressing, but not limited to, the following themes:- Natural product isolation, purification, structural characterization, and preliminary bioactivity screening- Biosynthetic gene clusters, pathway engineering, and metabolic optimization of natural product inspired scaffolds- Bioactivity guided fractionation and identification of lead natural products for therapeutic development- Bioactivity guided synthesis and structural optimization of natural product analogs- Stereoselective synthesis, semi synthesis, scaffold modification, and rational molecular design for enhanced potency and target selectivity- Structure–activity relationship (SAR) studies in cancer and neurodegenerative drug discovery, anchored to a defined natural product parent compound- Cellular and molecular mechanisms of enzyme inhibition, signaling pathway modulation, and epigenetic regulation- Natural product inspired modulators of neuroinflammation, oxidative stress, mitochondrial dysfunction, autophagy, ferroptosis, and apoptotic pathways- Target identification, target deconvolution, target validation, and molecular pharmacology of natural product derived scaffolds- Chemical biology approaches for elucidating mechanisms of action and therapeutic targets- Multi target and polypharmacological strategies inspired by natural products- Computational chemistry, molecular modeling, molecular dynamics, AI and machine learning assisted approaches, and bioinformatics tools for analog design and optimization- Natural product inspired compounds targeting cancer stem cells, tumor microenvironment remodeling, and drug resistance mechanisms- Discovery and optimization of compounds with improved pharmacokinetic properties, ADME profiles, and blood–brain barrier penetration- Biomarker guided studies and systems biology approaches for understanding therapeutic responses- Translational studies linking bioactive natural product analogs to therapeutic outcomes in cellular, animal, and clinical models- Emerging therapeutic modalities inspired by natural products, including covalent inhibitors, molecular glues, targeted protein degradation technologies (PROTACs), and other innovative chemical biology approaches, provided the core warhead or scaffold is derived from a natural product sourceBy integrating advances in natural product chemistry, synthetic and medicinal chemistry, chemical biology, mechanistic pharmacology, computational drug discovery, and translational therapeutics, this Research Topic seeks to provide a comprehensive platform for showcasing innovative research that transforms natural product inspired molecules into next generation therapeutics for cancer and neurodegenerative diseases. The collection aims to foster interdisciplinary collaboration and accelerate the translation of natural product derived discoveries into clinically relevant therapeutic interventions. Topic editors: Nageswara Rao Chintada, Mohammad Abrar Alam, Gothai Sivapragasam Source: https://www.frontiersin.org/research-topics/83254/natural-product-inspired-small-molecules-for-cancer-and-neurodegeneration-from-synthesis-to-therapeutic-mechanisms