Structure-guided and natural product-derived small molecules as antibiotic and anticancer agents

2018 ◽  
Vol 07 ◽  
Author(s):  
Rongshi Li
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Anticancer Agents

Medicinal Chemistry Database GDBMedChem

2019 ◽  
Author(s):  
Mahendra Awale ◽  
Finton Sirockin ◽  
Nikolaus Stiefl ◽  
Jean-Louis Reymond
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Medicinal Chemistry ◽  
3D Visualization ◽  
Molecular Size ◽  
Similarity Searching ◽  
Complex Molecules ◽  
Synthetic Accessibility ◽  
Simple Chemical ◽  
Reduced Complexity

<div>The generated database GDB17 enumerates 166.4 billion possible molecules up to 17 atoms of C, N, O, S and halogens following simple chemical stability and synthetic feasibility rules, however medicinal chemistry criteria are not taken into account. Here we applied rules inspired by medicinal chemistry to exclude problematic functional groups and complex molecules from GDB17, and sampled the resulting subset evenly across molecular size, stereochemistry and polarity to form GDBMedChem as a compact collection of 10 million small molecules.</div><div><br></div><div>This collection has reduced complexity and better synthetic accessibility than the entire GDB17 but retains higher sp 3 - carbon fraction and natural product likeness scores compared to known drugs. GDBMedChem molecules are more diverse and very different from known molecules in terms of substructures and represent an unprecedented source of diversity for drug design. GDBMedChem is available for 3D-visualization, similarity searching and for download at http://gdb.unibe.ch.</div>

scholarly journals Synthesis of Natural Product-Like Tricyclic Higher-Carbon Sugar Nucleosides

2021 ◽  
Vol 03 (01) ◽  
pp. e18-e22
Author(s):  
Xiao-Han Yuan ◽  
Shuai Wang ◽  
Xiao-Ning Wang ◽  
Bin Yu ◽  
Hong-Min Liu
Keyword(s):  
Natural Product ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Cancer Cell Lines ◽  
Starting Material ◽  
Target Compound

Because of the structural novelty and interesting biological profiles, the synthesis of higher-carbon sugars has been highly pursued. In this work, we first synthesized a series of structurally novel bis-uracil containing tricyclic higher-carbon sugar nucleosides (4a–e) using D-xylose as the starting material and the classical Vorbruggen glycosylation as the key synthetic step. The yields of the target compound were good. Unfortunately, despite the presence of pharmaceutically relevant uracil fragment, compounds 4a–e were inactive against the proliferation of several cancer cell lines (EC109, EC9706, PC-3, and MGC-803). Whether and how 4a–e functioned as anticancer agents would be further studied in our laboratory.

scholarly journals Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4250
Author(s):  
Xiao-Jing Pang ◽  
Xiu-Juan Liu ◽  
Yuan Liu ◽  
Wen-Bo Liu ◽  
Yin-Ru Li ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Phase I ◽  
Small Molecules ◽  
Anticancer Agents ◽  
Biological Function ◽  
Human Cancer ◽  
Tumor Cell Growth ◽  
Research Groups ◽  
Human Cancer Cell Lines ◽  
Opening Up

FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through “proteolysis targeting chimera” (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.

scholarly journals De Novo Drug Design Using Artificial Intelligence Applied on SARS-CoV-2 Viral Proteins ASYNT-GAN

BioChem ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 36-48
Author(s):  
Ivan Jacobs ◽  
Manolis Maragoudakis
Keyword(s):  
Deep Learning ◽  
Small Molecules ◽  
Natural Product ◽  
De Novo ◽  
Viral Proteins ◽  
Computer Assisted ◽  
De Novo Drug Design ◽  
Learning Techniques ◽  
Latent Space ◽  
Synthetic Molecule

Computer-assisted de novo design of natural product mimetics offers a viable strategy to reduce synthetic efforts and obtain natural-product-inspired bioactive small molecules, but suffers from several limitations. Deep learning techniques can help address these shortcomings. We propose the generation of synthetic molecule structures that optimizes the binding affinity to a target. To achieve this, we leverage important advancements in deep learning. Our approach generalizes to systems beyond the source system and achieves the generation of complete structures that optimize the binding to a target unseen during training. Translating the input sub-systems into the latent space permits the ability to search for similar structures, and the sampling from the latent space for generation.

Asymmetric Synthesis of 3,3′-Piperidinoyl Spirooxindoles and Discovery of Stereospecific Cycloadducts as Novel Hedgehog Pathway Modulators

Synthesis ◽  
2020 ◽  
Vol 52 (21) ◽  
pp. 3140-3152
Author(s):  
Kamal Kumar ◽  
Mohammad Rehan ◽  
Jana Flegel ◽  
Franziska Heitkamp ◽  
Jorgelina L. Pergomet ◽  
...  
Keyword(s):  
Transition Metal ◽  
Small Molecules ◽  
Asymmetric Synthesis ◽  
Natural Product ◽  
Transition Metal Complexes ◽  
Alder Reaction ◽  
Diels Alder ◽  
Hedgehog Pathway ◽  
Diels Alder Reaction ◽  
Efficient Access

An enantioselective hetero-Diels–Alder reaction of alkylidene­ oxindoles and 2-aza-3-silyloxy-1,3-butadienes, catalyzed by divalent transition metal complexes with N,N′-dioxide ligands offered an efficient access to natural-product-based 3,3′-piperidinoyl spiroox­indole class of small molecules. exo-Cycloadducts formed via stereospecific cycloaddition with Z-olefin displayed potent activity in modulation of hedgehog pathway.

A bifunctional pyrazolone–chromone synthon directed organocatalytic double Michael cascade reaction: forging five stereocenters in structurally diverse hexahydroxanthones

2019 ◽  
Vol 6 (9) ◽  
pp. 1485-1490 ◽  
Author(s):  
Xiong-Li Liu ◽  
Xiong Zuo ◽  
Jun-Xin Wang ◽  
Shun-qin Chang ◽  
Qi-Di Wei ◽  
...  
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Cascade Reaction

The merging of two or more known natural product-based scaffolds is a powerful and routine strategy to develop bioactive small molecules.

scholarly journals A Systematic Review of Recently Reported Marine Derived Natural Product Kinase Inhibitors

Marine Drugs ◽  
2019 ◽  
Vol 17 (9) ◽  
pp. 493 ◽  
Author(s):  
Li ◽  
Wang ◽  
Zhang ◽  
Zhang ◽  
Sajeevan ◽  
...  
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Disease States ◽  
Clinical Drugs ◽  
Kinase Inhibitory Activity ◽  
New Compounds ◽  
Further Development

Protein kinases are validated drug targets for a number of therapeutic areas, as kinase deregulation is known to play an essential role in many disease states. Many investigated protein kinase inhibitors are natural product small molecules or their derivatives. Many marine-derived natural products from various marine sources, such as bacteria and cyanobacteria, fungi, animals, algae, soft corals, sponges, etc. have been found to have potent kinase inhibitory activity, or desirable pharmacophores for further development. This review covers the new compounds reported from the beginning of 2014 through the middle of 2019 as having been isolated from marine organisms and having potential therapeutic applications due to kinase inhibitory and associated bioactivities. Moreover, some existing clinical drugs based on marine-derived natural product scaffolds are also discussed.

scholarly journals Novel 11-Substituted Ellipticines as Potent Anticancer Agents with Divergent Activity against Cancer Cells

2019 ◽  
Vol 12 (2) ◽  
pp. 90 ◽  
Author(s):  
Charlotte M. Miller ◽  
Elaine C. O’Sullivan ◽  
Florence O. McCarthy
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Natural Product ◽  
Anticancer Agents ◽  
Cellular Growth ◽  
Growth Effects

Ellipticines have well documented anticancer activity, in particular with substitution at the 1-, 2-, 6- and 9-positions. However, due to limitations in synthesis and coherent screening methodology the full SAR profile of this anticancer class has not yet been achieved. In order to address this shortfall, we have set out to explore the anticancer activity of this potent natural product by substitution. We currently describe the synthesis of novel 11-substituted ellipticines with two specific derivatives showing potency and diverging cellular growth effects.

Alkynyl Prins and Alkynyl Aza-Prins Annulations: Scope and Synthetic Applications

Synthesis ◽  
2020 ◽  
Vol 52 (14) ◽  
pp. 1991-2007 ◽  
Author(s):  
Alison J. Frontier ◽  
Shukree Abdul-Rashed ◽  
Connor Holt
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Natural Product ◽  
Natural Product Synthesis ◽  
Pericyclic Reactions ◽  
Prins Reaction ◽  
Prins Cyclization ◽  
Synthetic Utility ◽  
Cascade Processes ◽  
Saturated Heterocycles

This review focuses on alkynyl Prins and alkynyl aza-Prins cyclization­ processes, which involve intramolecular coupling of an alkyne with either an oxocarbenium or iminium electrophile. The oxocarbenium or iminium species can be generated through condensation- or elimination-type processes, to achieve an overall bimolecular annulation that enables the synthesis of both oxygen- and nitrogen-containing­ saturated heterocycles with different ring sizes and substitution patterns. Also discussed are cascade processes in which alkynyl Prins heterocyclic adducts react to trigger subsequent pericyclic reactions, including [4+2] cycloadditions and Nazarov electrocyclizations, to rapidly construct complex small molecules. Finally, examples of the use of alkynyl Prins and alkynyl aza-Prins reactions in the synthesis of natural products are described. The review covers the literature through the end of 2019.1 Introduction1.1 Alkyne-Carbonyl Coupling Pathways1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles)2.1 Early Work2.2 Halide as Terminal Nucleophile2.3 Oxygen as Terminal Nucleophile2.4 Arene as Terminal Nucleophile (Intermolecular)2.5 Arene Terminal Nucleophile (Intramolecular)2.6 Cyclizations Terminated by Elimination3 Synthetic Utility of Alkynyl Prins Annulation3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo­- addition­-Oxidation Sequence3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors3.3 Alkynyl Prins Cyclization in Natural Product Synthesis4 Alkynyl Aza-Prins Annulation4.1 Iminium Electrophiles4.2 Activated Iminium Electrophiles5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis6 Summary and Outlook

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