Discovering Promising Anti-cancer Drug Candidates from Marine Algae

<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>

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

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.642 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 642-642 ◽

Cited By ~ 1

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.

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Industry Watch

Asia-Pacific Biotech News ◽

10.1142/s0219030309000391 ◽

2009 ◽

Vol 13 (06) ◽

pp. 36-54 ◽

Cited By ~ 1

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.

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

Molecules ◽

10.3390/molecules24091749 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1749 ◽

Cited By ~ 1

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.

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Development of a Cell-Based Assay to Quantify the Inflammatory Potential of Test Substances and Screen Compound Libraries for Anti-cancer Drug Candidates in a High-Throughput Format

Methods in Molecular Biology™ - Inflammation and Cancer ◽

10.1007/978-1-60327-530-9_9 ◽

2009 ◽

pp. 159-167 ◽

Cited By ~ 1

Author(s):

Serguei V. Kozlov

Keyword(s):

High Throughput ◽

Cancer Drug ◽

Drug Candidates ◽

Compound Libraries ◽

Anti Cancer ◽

A Cell

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Is inflammatory micronucleation the key to a successful anti-mitotic cancer drug?

Open Biology ◽

10.1098/rsob.170182 ◽

2017 ◽

Vol 7 (11) ◽

pp. 170182 ◽

Cited By ~ 23

Author(s):

T. J. Mitchison ◽

J. Pineda ◽

J. Shi ◽

S. Florian

Keyword(s):

Dna Damage ◽

T Cell ◽

Cancer Cells ◽

Cancer Drug ◽

Tumour Regression ◽

Two Dimensional ◽

Drug Candidates ◽

Cell Responses ◽

Anti Cancer ◽

Inflammatory Signalling

Paclitaxel is a successful anti-cancer drug that kills cancer cells in two-dimensional culture through perturbation of mitosis, but whether it causes tumour regression by anti-mitotic actions is controversial. Drug candidates that specifically target mitosis, including inhibitors of kinesin-5, AurkA, AurkB and Plk1, disappointed in the clinic. Current explanations for this discrepancy include pharmacokinetic differences and hypothetical interphase actions of paclitaxel. Here, we discuss post-mitotic micronucleation as a special activity of taxanes that might explain their higher activity in solid tumours. We review data showing that cells which exit mitosis in paclitaxel are highly micronucleated and suffer post-mitotic DNA damage, and that these effects are much stronger for paclitaxel than kinesin-5 inhibitors. We propose that post-mitotic micronucleation promotes inflammatory signalling via cGAS–STING and other pathways. In tumours, this signalling may recruit cytotoxic leucocytes, damage blood vessels and prime T-cell responses, leading to whole-tumour regression. We discuss experiments that are needed to test the micronucleation hypothesis, and its implications for novel anti-mitotic targets and enhancement of taxane-based therapies.

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