scholarly journals Fragment-Based Approach towards the Design of Potent and Versatile Anti-Cancer Agents

2020 ◽  
Vol V (I) ◽  
pp. 1-14
Author(s):  
Sana Ali Zahra ◽  
Ayesha Imran ◽  
Faiza Khalid ◽  
Mubashir Rehman
Keyword(s):  
Anticancer Agents ◽  
Computational Method ◽  
Cancer Drug ◽  
Drug Candidates ◽  
Fragment Screening ◽  
Fragment Library ◽  
Anti Cancer ◽  
Hsp 90 ◽  
Hit Identification ◽  
Fragment Based Drug Discovery

Despite years of clinical research and trials of encouraging new therapies, cancer remains a leading cause of morbidity and mortality. The fragment-based drug discovery has evolved formerly as an efficient approach for identification, optimization, and generation of lead. After identifying the fragments having binding affinity with the target using computational method for fragment screening, they are optimized into more active compounds. This review elaborates the application of methodology of fragment-based drug design in designing potent and versatile anti-cancer drug candidates. It comprises of details such as construction of fragment library and screening, principles of library design, fragment hit identification, fragment to lead optimization, deconstruction and reconstruction approach, unified fragment based QSAR technique, phytochemical and pharmacophoric fragment based drug development and FBDD based targeting of epigenetic regulators in cancer. The agents discussed include STAT-3 inhibitor, vemurafenib, pazopanib, TAS-116 HSP-90 α/β inhibitor, pexidartinib, venetoclax and erdafitinib, FBDD based designed Anticancer Agents.

Diverse thiophenes as scaffolds in anti-cancer drug development: A concise review

2020 ◽  
Vol 20 ◽  
Author(s):  
Neha V. Bhilare ◽  
Pratibha B. Auti ◽  
Vinayak S. Marulkar ◽  
Vilas J. Pise
Keyword(s):  
Drug Development ◽  
Anticancer Agents ◽  
Heterocyclic Ring ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Cancer Drug ◽  
Active Compounds ◽  
Natural Origin ◽  
Concise Review ◽  
Anti Cancer

: Thiophenes are one among the abundantly found heterocyclic ring systems in many biologically active compounds. Moreover various substituted thiophenes exert numerous pharmacological actions on account of their isosteric resemblance with compounds of natural origin thus rendering them with diverse actions like antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antiallergic, hypotensives etc.. In this review we specifically explore the chemotherapeutic potential of variety of structures consisting of thiophene scaffolds as prospective anticancer agents.

Multi-Targeting Anticancer Agents: Rational Approaches, Synthetic Routes and Structure Activity Relationship

2019 ◽  
Vol 19 (7) ◽  
pp. 842-874 ◽  
Author(s):  
Harbinder Singh ◽  
Nihar Kinarivala ◽  
Sahil Sharma
Keyword(s):  
Anticancer Agents ◽  
Cancer Drug ◽  
Design And Synthesis ◽  
Cancer Drug Discovery ◽  
Dual Targeting ◽  
Structure Activity ◽  
Anti Cancer ◽  
Dual Inhibitors ◽  
Recent Trends ◽  
Synthetic Routes

We live in a world with complex diseases such as cancer which cannot be cured with one-compound one-target based therapeutic paradigm. This could be due to the involvement of multiple pathogenic mechanisms. One-compound-various-targets stratagem has become a prevailing research topic in anti-cancer drug discovery. The simultaneous interruption of two or more targets has improved the therapeutic efficacy as compared to the specific targeted based therapy. In this review, six types of dual targeting agents along with some interesting strategies used for their design and synthesis are discussed. Their pharmacology with various types of the molecular interactions within their specific targets has also been described. This assemblage will reveal the recent trends and insights in front of the scientific community working in dual inhibitors and help them in designing the next generation of multi-targeted anti-cancer agents.

scholarly journals Fragment Library of Natural Products and Compound Databases for Drug Discovery

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1518 ◽  
Author(s):  
Ana L. Chávez-Hernández ◽  
Norberto Sánchez-Cruz ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Synthetic Compounds ◽  
Drug Candidates ◽  
Compound Libraries ◽  
Chemical Database ◽  
Fragment Library ◽  
Further Development ◽  
Fragment Libraries ◽  
Fragment Based Drug Discovery

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity.

Fragment-based drug design of nature-inspired compounds

2019 ◽  
Vol 4 (9) ◽  
Author(s):  
Abdulkarim Najjar ◽  
Abdurrahman Olğaç ◽  
Fidele Ntie-Kang ◽  
Wolfgang Sippl
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Pocket ◽  
Biological Macromolecules ◽  
Drug Candidates ◽  
Fragment Screening ◽  
Small Molecule Drugs ◽  
Lead Generation ◽  
Hit Identification

Abstract Natural product (NP)-derived drugs can be extracts, biological macromolecules, or purified small molecule substances. Small molecule drugs can be originally purified from NPs, can represent semisynthetic molecules, natural fragments containing small molecules, or are fully synthetic molecules that mimic natural compounds. New semisynthetic NP-like drugs are entering the pharmaceutical market almost every year and reveal growing interests in the application of fragment-based approaches for NPs. Thus, several NP databases were constructed to be implemented in the fragment-based drug design (FBDD) workflows. FBDD has been established previously as an approach for hit identification and lead generation. Several biophysical and computational methods are used for fragment screening to identify potential hits. Once the fragments within the binding pocket of the protein are identified, they can be grown, linked, or merged to design more active compounds. This work discusses applications of NPs and NP scaffolds to FBDD. Moreover, it briefly reviews NP databases containing fragments and reports on case studies where the approach has been successfully applied for the design of antimalarial and anticancer drug candidates.

scholarly journals Defining desirable natural product derived anticancer drug space: optimization of molecular physicochemical properties and ADMET attributes

ADMET & DMPK ◽  
2016 ◽  
Vol 4 (2) ◽  
pp. 98 ◽  
Author(s):  
Deepika Singh
Keyword(s):  
Hydrogen Bond ◽  
Natural Products ◽  
Physicochemical Properties ◽  
Natural Product ◽  
Aqueous Solubility ◽  
Cancer Drug ◽  
Log P ◽  
Drug Candidates ◽  
Anti Cancer ◽  
Property Space

<p class="ADMETabstracttext">As part of our endeavor to enhance survival of natural product derived drug candidates and to guide the medicinal chemist to design higher probability space for success in the anti cancer drug development area, we embarked on a detailed study of the property space for a collection of natural product derived anti cancer molecules. We carried out a comprehensive analysis of properties for 24 natural products derived anti cancer drugs including clinical development candidates and a set of 27 natural products derived anti cancer lead compounds. In particular, we focused on understanding the interplay among eight physicochemical properties including like partition coefficient (log P), distribution coefficient at pH=7.4 (log D), topological polar surface area (TPSA), molecular weight (MW), aqueous solubility (log S), number of hydrogen bond acceptors (HBA), number of hydrogen bond donors (HBD) and number of rotatable bonds (n<sub>Rot</sub>) crucial for drug design and  relationships between physicochemical properties, ADME (absorption, distribution, metabolism, and elimination) attributes, and in silico toxicity profile for these two sets of compounds. This analysis provides guidance for the chemist to modify the existing natural product scaffold or designing of new anti cancer molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.</p>

Screening of 129 FDA approved anti-cancer drugs in colorectal cancer cell lines resistant to oxaliplatin or irinotecan (SN38).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 642-642 ◽  
Author(s):  
Jan Stenvang ◽  
Christine Hjorth Andreassen ◽  
Nils Brünner
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cell Viability ◽  
Cell Line ◽  
Cell Lines ◽  
Resistant Cell ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Drug Candidates ◽  
Anti Cancer

642 Background: In metastatic colorectal cancer (mCRC) only 3 cytotoxic drugs (oxaliplatin, irinotecan and fluorouracil (5-FU)) are approved and the first and second line response rates are about 50% and 10-15%, respectively. Thus, new treatment options are needed. Novel anti-cancer drug candidates are primarily tested in an environment of drug resistance and the majority of novel drug candidates fail during clinical development. Therefore, “repurposing” of drugs has emerged as a promising strategy to apply established drugs in novel indications. The aim of this project was to screen established anti-cancer drugs to identify candidates for testing in mCRC patients relapsing on standard therapy. Methods: We applied 3 parental (drug sensitive) CRC cell lines (HCT116, HT29 and LoVo) and for each cell line also an oxaliplatin and irinotecan (SN38) resistant cell line. We obtained 129 FDA approved anti-cancer drugs from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) ( https://dtp.cancer.gov/ ). The parental HT29 cell line and the drug resistant sublines HT29-SN38 and HT29-OXPT were exposed to 3 concentrations of each of the anti-cancer drugs. The effect on cell viability was analyzed by MTT assays. Nine of the drugs were analyzed for effect in the LoVo and HCT116 and the SN38- and oxaliplatin-resistant derived cell lines. Results: None of the drugs caused evident differential response between the resistant and sensitive cells or between the SN38 and oxaliplatin resistant cells. The screening confirmed the resistance as the cells displayed resistance to drugs in the same class as the one they were made resistant to. Of the drugs, 45 decreased cell viability in the HT29 parental and oxaliplatin- or SN-38 resistant cell lines. Nine drugs were tested in all nine CRC cell lines and eight decrease cell viability in the nine cell lines. These included drugs in different classes such as epigenetic drugs, antibiotics, mitotic inhibitors and targeted therapies. Conclusions: This study revealed several possible new “repurposing” drugs for CRC therapy, by showing that 45 FDA-approved anti-cancer drugs decrease cell viability in CRC cell lines with acquired drug resistance.

Industry Watch

2009 ◽  
Vol 13 (06) ◽  
pp. 36-54 ◽  
Keyword(s):  
H1n1 Virus ◽  
Digital Pathology ◽  
Cancer Therapeutics ◽  
Strategic Partnership ◽  
Cancer Drug ◽  
Purchase Order ◽  
Republic Of China ◽  
Drug Candidates ◽  
Anti Cancer ◽  
Stem Cell Treatment

"Off-The-Shelf" Stem Cell Treatment for Heart Failure. Cytopia Cancer Program Reaches Important Milestone at Cancer Therapeutics CRC. Starpharma and Elanco Agree to Develop New Products. China Sky One Medical, Inc. Achieves Significant Breakthrough In Sudden Cardiac Death (SCD) Early Examination Kit. Roche Applied Science Opens Application Support Center in Shanghai. Luminex Expands Globally and Opens Facility in People's Republic of China. Genesis Pharmaceuticals Launches Three New TCM Products. China Sky One Medical, Inc. to Develop New Anti-Cancer Drug with Taiwan Golden Biotechnology Corp. Solvay Pharmaceuticals Announces Strategic Partnership with HUYA to Access New Drug Candidates From China. Sinovac Receives $US12.9 mn Purchase Order for Healive® from China's Ministry of Public Health. GE Launches Lullaby Warmer for Newborn in India. SymBio Pharmaceuticals Limited and Eisai Co., Ltd. Conclude License Agreement for Bendamustine Hydrochloride (SyB L-0501) in Korea and Singapore. Aperio Expands Global Digital Pathology Presence with New Subsidiary in Asia. Valeant Pharmaceuticals Grants Schering-Plough Exclusive Option in Japan for Taribavirin in Exchange. Genome Institute of Singapore and Roche NimbleGen Develop Rapid Approach to Identify H1N1 Virus Mutations and Resistance to Drugs.

scholarly journals Design and Synthesis of Flavonoidal Ethers and Their Anti-Cancer Activity In Vitro

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1749 ◽  
Author(s):  
Lu Jin ◽  
Meng-Ling Wang ◽  
Yao Lv ◽  
Xue-Yi Zeng ◽  
Chao Chen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Cancer Drug ◽  
Hydroxyl Groups ◽  
Drug Candidates ◽  
Design And Synthesis ◽  
Anti Cancer ◽  
Clinical Drugs

Flavonoids are well-characterized polyphenolic compounds with pharmacological and therapeutic activities. However, most flavonoids have not been developed into clinical drugs, due to poor bioavailability. Herein, we report a strategy to increase the drugability of flavonoids by constructing C(sp2)-O bonds and stereo- as well as regioselective alkenylation of hydroxyl groups of flavonoids with ethyl-2,3-butadienoate allenes. Twenty-three modified flavonoid derivatives were designed, synthesized, and evaluated for their anti-cancer activities. The results showed that compounds 4b, 4c, 4e, 5e, and 6b exhibited better in vitro inhibitory activity against several cancer cell lines than their precursors. Preliminary structure–activity relationship studies indicated that, in most of the cancer cell lines evaluated, the substitution on position 7 was essential for increasing cytotoxicity. The results of this study might facilitate the preparation or late-stage modification of complex flavonoids as anti-cancer drug candidates.

scholarly journals Discovering Promising Anti-cancer Drug Candidates from Marine Algae

2018 ◽  
Vol 6 (2) ◽  
pp. 44-50 ◽  
Author(s):  
A. Joseph Thatheyus ◽  
N. Jennifer Michelli Kiruba ◽  
M. Andrew Pradeep
Keyword(s):  
Marine Algae ◽  
Cancer Drug ◽  
Drug Candidates ◽  
Anti Cancer
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