ADMET profiling of geographically diverse phytochemical using chemoinformatic tools

Aim: Phytocompounds are important due to their uniqueness, however, only few reach the development phase due to their poor pharmacokinetics. Therefore, preassessing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties is essential in drug discovery. Methodology: Biologically diverse databases (Phytochemica, SerpentinaDB, SANCDB and NuBBEDB) covering the region of India, Brazil and South Africa were considered to predict the ADMET using chemoinformatic tools (Qikprop, pkCSM and DataWarrior). Results: Screening through each of pharmacokinetic criteria resulted in identification of 24 compounds that adhere to all the ADMET properties. Furthermore, assessment revealed that five have potent anticancer biological activity against cancer cell lines. Conclusion: We have established an open-access database (ADMET-BIS) to enable identification of promising molecules that follow ADMET properties and can be considered for drug development.

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Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation

Medicinal Chemistry ◽

10.2174/1573406416666200420081540 ◽

2020 ◽

Vol 16 ◽

Author(s):

Tran Khac Vu ◽

Nguyen Thi Thanh ◽

Nguyen Van Minh ◽

Nguyen Huong Linh ◽

Nguyen Thi Phương Thao ◽

...

Keyword(s):

Drug Discovery ◽

Cell Lines ◽

Cancer Cell ◽

Hdac Inhibitors ◽

Cancer Cell Lines ◽

Hydroxamic Acids ◽

Biological Evaluation ◽

Hdac Inhibition ◽

Ic50 Value ◽

Mcf 7

Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. Aims: This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Method: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin-4(3H)- ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structure-activity. relationships. Results: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. Conclusion: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

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Synthesis of Novel Tryptamine Derivatives and Their Biological Activity as Antitumor Agents

Molecules ◽

10.3390/molecules26030683 ◽

2021 ◽

Vol 26 (3) ◽

pp. 683

Author(s):

Giorgia Simonetti ◽

Carla Boga ◽

Joseph Durante ◽

Gabriele Micheletti ◽

Dario Telese ◽

...

Keyword(s):

Biological Activity ◽

Cell Lines ◽

Cancer Cell ◽

Solid Tumor ◽

Antitumor Agents ◽

Cancer Cell Lines ◽

Hematological Cancer ◽

Selective Effect ◽

Ht29 Cells ◽

High Level

We synthesized five novel tryptamine derivatives characterized by the presence of an azelayl chain or of a 1,1,1-trichloroethyl group, in turn connected to another heterocyclic scaffold. The combination of tryptamin-, 1,1,1-trichloroethyl- and 2-aminopyrimidinyl- moieties produced compound 9 identified as the most active compound in hematological cancer cell lines (IC50 = 0.57–65.32 μM). Moreover, keeping constant the presence of the tryptaminic scaffold and binding it to the azelayl moiety, the compounds maintain biological activity. Compound 13 is still active against hematological cancer cell lines and shows a selective effect only on HT29 cells (IC50 = 0.006 µM) among solid tumor models. Compound 14 loses activity on all leukemic lines, while showing a high level of toxicity on all solid tumor lines tested (IC50 0.0015–0.469 µM).

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Synthesis, conformational preferences, and biological activity of conformational analogues of the microtubule-stabilizing agents, (−)-zampanolide and (−)-dactylolide

MedChemComm ◽

10.1039/c9md00164f ◽

2019 ◽

Vol 10 (5) ◽

pp. 800-805 ◽

Cited By ~ 2

Author(s):

Jeffrey L. Henry ◽

Matthew R. Wilson ◽

Michael P. Mulligan ◽

Taylor R. Quinn ◽

Dan L. Sackett ◽

...

Keyword(s):

Biological Activity ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Stabilizing Agents ◽

Conformational Preferences

Zampanolide and dactylolide are microtubule-stabilizing polyketides possessing potent cytotoxicity towards a variety of cancer cell lines.

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Synthesis of Novel Class of N-Alkyl-isatin-3-iminobenzoic Acid Derivatives and Their Biological Activity in Zebrafish Embryos and Human Cancer Cell Lines

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b17-00674 ◽

2018 ◽

Vol 41 (3) ◽

pp. 350-359 ◽

Cited By ~ 7

Author(s):

Muhammad Farooq ◽

Zainab Mohammed Al Marhoon ◽

Nael Abu Taha ◽

Almohannad Abdulrahman Baabbad ◽

Mohammed Ahmed Al-Wadaan ◽

...

Keyword(s):

Biological Activity ◽

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Zebrafish Embryos ◽

Human Cancer Cell ◽

Human Cancer Cell Lines

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Synthesis, Expression and Biological Activity of the Prohormone for Gastrin Releasing Peptide (ProGRP)

Endocrinology ◽

10.1210/en.2005-0574 ◽

2006 ◽

Vol 147 (1) ◽

pp. 502-509 ◽

Cited By ~ 24

Author(s):

Chelsea Dumesny ◽

Oneel Patel ◽

Shamilah Lachal ◽

Andrew S. Giraud ◽

Graham S. Baldwin ◽

...

Keyword(s):

Colon Cancer ◽

Biological Activity ◽

Cell Lines ◽

Cancer Cell ◽

Inositol Phosphate ◽

Cancer Cell Lines ◽

Colon Cancer Cell ◽

Biologically Active ◽

Gastrin Releasing Peptide ◽

End Products

Gastrin-releasing peptide (GRP) has a widespread distribution and multiple stimulating effects on endocrine and exocrine secretions and metabolism. The prohormone for GRP (ProGRP, 125 amino acids) is processed to the amidated, biologically active end products GRP1–27 and GRP18–27. Amidated forms of GRP are putative autocrine or paracrine growth factors in a number of cancers including colorectal cancer. However, the potential role and biological activity of proGRP has not been investigated. Using a newly developed antisera directed to the N terminus of human proGRP, proGRP immunoreactivity was detected in all of the endometrial, prostate, and colon cancer cell lines tested and in nine of 10 resected colorectal carcinomas. However, no amidated forms were detected, suggesting an attenuation of processing in tumors. Recombinant proGRP was expressed as a His-tag fusion protein and purified by metal affinity chromatography and HPLC. ProGRP stimulated proliferation of a colon cancer cell line and activated MAPK, but unlike GRP18–27amide had no effect on inositol phosphate production. ProGRP did not compete with iodinated bombesin in binding assays on Balb-3T3 cells transfected with the known GRP receptors, GRP-R or BRS-3. We conclude that proGRP is present in a number of cancer cell lines and in resected colorectal tumors and is biologically active. Our results suggest that antagonists to GRP precursors rather than the amidated end products should be developed as a treatment for colorectal and other cancers that express proGRP-derived peptides.

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Synthesis, structure, magnetic and biological activity studies of bis-hydrazone derived Cu(ii) and Co(ii) coordination compounds

Dalton Transactions ◽

10.1039/c6dt01496h ◽

2016 ◽

Vol 45 (29) ◽

pp. 11849-11863 ◽

Cited By ~ 16

Author(s):

Upendarrao Golla ◽

Amit Adhikary ◽

Amit Kumar Mondal ◽

Raghuvir Singh Tomar ◽

Sanjit Konar

Keyword(s):

Biological Activity ◽

Cell Lines ◽

Cancer Cell ◽

Coordination Compounds ◽

Linear Chain ◽

Nuclease Activity ◽

Cancer Cell Lines ◽

Magnetic Studies ◽

Synthetic Strategy ◽

Chain Compound

Three double stranded helicates and one linear chain compound have been synthesized following similar synthetic strategy with change in the coordination of the ligands. Magnetic studies, nuclease activity and cytotoxicity on mammalian cancer cell lines have been investigated.

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6-Substituted imidazo[1,2-a]pyridines: Synthesis and biological activity against colon cancer cell lines HT-29 and Caco-2

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2011.07.036 ◽

2011 ◽

Vol 46 (9) ◽

pp. 4573-4583 ◽

Cited By ~ 58

Author(s):

Nurit Dahan-Farkas ◽

Candice Langley ◽

Amanda L. Rousseau ◽

Dharmendra B. Yadav ◽

Hajierah Davids ◽

...

Keyword(s):

Colon Cancer ◽

Biological Activity ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Colon Cancer Cell ◽

Colon Cancer Cell Lines ◽

Ht 29

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Abstract 1918: InnoPanelTM-a well characterized panel of 1000 cancer cell lines for anticancer drug development

10.1158/1538-7445.sabcs18-1918 ◽

2019 ◽

Author(s):

Feng Hao ◽

Changpeng Liu ◽

Hao Peng ◽

Xiaolin Zhou ◽

Yunhui Fu ◽

...

Keyword(s):

Drug Development ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Drug ◽

Cancer Cell Lines ◽

Anticancer Drug Development

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Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function

Life Science Alliance ◽

10.26508/lsa.201900431 ◽

2019 ◽

Vol 2 (5) ◽

pp. e201900431 ◽

Cited By ~ 6

Author(s):

Walaa E Kattan ◽

Wei Chen ◽

Xiaoping Ma ◽

Tien Hung Lan ◽

Dharini van der Hoeven ◽

...

Keyword(s):

Biological Activity ◽

Plasma Membrane ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Lipid Binding ◽

Small Gtpase ◽

Membrane Anchor ◽

Normal Cells

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We, therefore, investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidyl-4-phosphate synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion significantly reduced proliferation and anchorage-independent growth of multiple KRAS-dependent cancer cell lines, and attenuated KRAS signaling in vivo. Similarly, functionally inhibiting ORP5 and ORP8 by inhibiting PI4KIIIα-mediated synthesis of phosphatidyl-4-phosphate at the PM selectively inhibited the growth of KRAS-dependent cancer cell lines over normal cells. Inhibiting KRAS function through regulating PM lipid PtdSer content may represent a viable strategy for KRAS-driven cancers.

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