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>

scholarly journals Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

2020 ◽  
Author(s):  
Yuvixza Lizarme-Salas ◽  
Alexandra Daryl Ariawan ◽  
Ranjala Ratnayake ◽  
Hendrik Luesch ◽  
Angela Finch ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Natural Product ◽  
Inhibitory Activity ◽  
Drug Target ◽  
Medicinal Chemistry ◽  
Biological Activities ◽  
Aqueous Solubility ◽  
Hydrocarbon Chain ◽  
Lead Compound ◽  
Enhanced Solubility

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.

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 Marine natural products

2017 ◽  
Vol 34 (3) ◽  
pp. 235-294 ◽  
Author(s):  
John W. Blunt ◽  
Brent R. Copp ◽  
Robert A. Keyzers ◽  
Murray H. G. Munro ◽  
Michèle R. Prinsep
Keyword(s):  
Natural Products ◽  
Absolute Configuration ◽  
Marine Natural Products ◽  
Cancer Drug ◽  
Anti Cancer ◽  
New Compounds

This review of marine natural products for 2015 describes 1340 new compounds and reports structural revisions or assignments of absolute configuration for previously reported compounds. Other aspects of marine natural products research over the three sesquidecades from 1971 are also examined and contrasted against the 2015 discovery of the source of ET-743, also known as the anti-cancer drug Yondelis®(trabectedin).

scholarly journals Synthesis of Mutual Prodrugs of Secnidazole and Ciprofloxacin and study Their Physicochemical Properties

2021 ◽  
Vol 30 (1) ◽  
pp. 133-143
Author(s):  
Marwah W. Khalid ◽  
Leaqaa Abd ◽  
Ahmed N. Abood
Keyword(s):  
Physicochemical Properties ◽  
Aqueous Solubility ◽  
Fold Increase ◽  
Antibacterial Activities ◽  
Log P ◽  
Klebsiella Pneumonia ◽  
Bacterial Strains ◽  
Structural Modifications ◽  
Chemical Hydrolysis ◽  
Ft Ir

  Secnidazole was linked with ciprofloxacin as mutual prodrugs to get antibiotics with broader spectrum of activity, improved physicochemical properties and given by single dose to improve patient’s compliance. Furthermore, they provide structural modifications to overcome bacterial adaptation. The structures of the synthesized compounds were confirmed using FT-IR, mass spectrometry, elemental microanalysis (CHNO) and some physiochemical properties. This modification was led to an increase in Log P values for Mutual I (Log P 1.114) and Mutual II (Log P 1.97) compared with its values for Secnidazole (Log P -0.373) and ciprofloxacin (Log P -0.832). The solubility of prodrugs had been determined in different media, Mutual II showed 144-fold increase in aqueous solubility compared to ciprofloxacin. Taste evaluation by panel method showed palatable taste in prodrugs compared to the parent drugs. The synthesized compounds were screened for their antimicrobial activity against different bacterial strains which are, Staphylococcus aureus, Pseudomonas aeruginosa, E. coli and Klebsiella pneumonia. The prodrugs have revealed excellent antibacterial activities compared with the parent compounds. Chemical hydrolysis study at pH (1.2 and 7.4) has indicated that these compounds may pass unhydrolyzed through the stomach and produce enough stability to be absorbed from the intestine as indicated by t1/2 values.

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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