Synthesis and Biological Evaluation of Novel Osthol Derivatives as Potent Cytotoxic Agents

Background: Natural product, osthol has been found to have important biological and pharmacological roles particularly having inhibitory effect on multiple types of cancer. Objective: The unmet needs in cancer therapeutics make its derivatization an important and exciting field of research. Keeping this in view, a whole new series of diverse analogues of osthol (1) were synthesized. Method: All the newly synthesized compounds were made through modification in the lactone ring as well as in the side chain of the osthol molecule and were subjected to anti-proliferative screening through 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) against four different human cancers of diverse origins viz. Colon (Colo-205), lung (A549), Leukemia (THP- 1) and breast (MCF-7) including SV40 transformed normal breast epithelial cell (fR-2). Results: Interestingly, among the tested molecules, most of the analogs displayed better antiproliferative activity than the parent Osthol 1. However, among all the tested analogs, compound 28 exhibited the best results against leukemia (THP1) cell line with IC50 of 5µM.Compound 28 induced potent apoptotic effects and G1 phase arrest in leukemia cancer cells (THP1). The population of apoptotic cells increased from 13.8% in negative control to 26.9% at 8μM concentration of 28. Compound 28 also induced a remarkable decrease in mitochondrial membrane potential (ΛΨm) leading to apoptosis of the cancer cells. Conclusion: A novel series of molecules derived from natural product osthol were synthesized, wherein compound 28 was found to be most effective against leukemia and with 10 fold less toxicity against normal cells. The compound induced cancer inhibition mainly through apoptosis and thus has a potential in cancer therapeutics.

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Design, synthesis, and biological evaluation of new series of 2-amido-1,3,4-thiadiazole derivatives as cytotoxic agents

Zeitschrift für Naturforschung B ◽

10.1515/znb-2015-0138 ◽

2016 ◽

Vol 71 (3) ◽

pp. 205-210 ◽

Cited By ~ 3

Author(s):

Ali Almasirad ◽

Loghman Firoozpour ◽

Maliheh Nejati ◽

Najmeh Edraki ◽

Omidreza Firuzi ◽

...

Keyword(s):

Human Tumor ◽

Inhibitory Effect ◽

Biological Evaluation ◽

Cytotoxic Agents ◽

Antitumor Activities ◽

Design Synthesis ◽

Ethidium Bromide Staining ◽

Thiadiazole Derivatives ◽

Synthesis And Biological Evaluation

AbstractA series of novel 1,3,4-thiadiazole derivatives bearing an amide moiety were designed, synthesized, and evaluated for their in vitro antitumor activities against HL-60, SKOV-3 and MOLT-4 human tumor cell lines by MTT assay. Ethyl 2-((5-(4-methoxybenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5f) showed the best inhibitory effect against SKOV-3 cells, with an IC50 value of 19.5 μm. In addition, the acridine orange/ethidium bromide staining assay in SKOV-3 cells suggested that the cytotoxic activity of 5f occurs via apoptosis.

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Synthesis and Biological Evaluation of BODIPY-PF-543

Molecules ◽

10.3390/molecules24234408 ◽

2019 ◽

Vol 24 (23) ◽

pp. 4408

Author(s):

Shrestha ◽

Hwang ◽

Lee ◽

Kim ◽

Oh ◽

...

Keyword(s):

Anticancer Activity ◽

Cancer Cells ◽

Intracellular Localization ◽

Sphingosine Kinase ◽

Inhibitory Effect ◽

Biological Evaluation ◽

Boron Dipyrromethene ◽

Sphingosine 1 Phosphate ◽

Synthesis And Biological Evaluation

Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron–dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect.

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Promise and Challenge of RNA Interference–Based Therapy for Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.6287 ◽

2011 ◽

Vol 29 (6) ◽

pp. 747-754 ◽

Cited By ~ 85

Author(s):

Fabio Petrocca ◽

Judy Lieberman

Keyword(s):

Rna Interference ◽

Cancer Cells ◽

Mammalian Cells ◽

Locally Advanced ◽

Cancer Therapeutics ◽

Cellular Transformation ◽

Cytotoxic Agents ◽

Cancer Drug ◽

Cell Surface Antigens ◽

Rnai Machinery

Cancer therapeutics still fall far short of our goals for treating patients with locally advanced or metastatic disease. Until recently, almost all cancer drugs were crude cytotoxic agents that discriminate poorly between cancer cells and normally dividing cells. The development of targeted biologics that recognize tumor cell surface antigens and of specific inhibitors of pathways dysregulated in cancer cells or normal cellular pathways on which a cancer cell differentially depends has provided hope for converting our increasing understanding of cellular transformation into intelligently designed anticancer therapeutics. However, new drug development is painfully slow, and the pipeline of new therapeutics is thin. The discovery of RNA interference (RNAi), a ubiquitous cellular pathway of gene regulation that is dysregulated in cancer cells, provides an exciting opportunity for relatively rapid and revolutionary approaches to cancer drug design. Small RNAs that harness the RNAi machinery may become the next new class of drugs for treating a variety of diseases. Although it has only been 9 years since RNAi was shown to work in mammalian cells, about a dozen phase I to III clinical studies have already been initiated, including four for cancer. So far there has been no unexpected toxicity and suggestions of benefit in one phase II study. However, the obstacles for RNAi-based cancer therapeutics are substantial. This article will discuss how the endogenous RNAi machinery might be harnessed for cancer therapeutics, why academic researchers and biotech and pharmaceutical companies are so excited, and what the obstacles are and how they might be overcome.

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Telomerase-directed molecular therapeutics

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399402004507 ◽

2002 ◽

Vol 4 (10) ◽

pp. 1-25 ◽

Cited By ~ 19

Author(s):

W. Nicol Keith ◽

Alan Bilsland ◽

T.R. Jeffry Evans ◽

Rosalind M. Glasspool

Keyword(s):

Cancer Cells ◽

Cancer Therapeutics ◽

Modern Medicine ◽

Cytotoxic Agents ◽

Western World ◽

Cancer Therapies ◽

Malignant Tumours ◽

Molecular Therapeutics ◽

Molecular Events ◽

Choice Of Treatment

The management of malignant disease remains one of the most challenging areas of modern medicine. The lifetime risk of developing cancer in the western world is estimated to be as high as 1 in 3. Traditionally, surgery, chemotherapy and radiotherapy have been the primary choice of treatment for patients with malignant tumours. Despite advances in the use and development of conventional cytotoxic agents, the cure rate remains disappointing in most patients with advanced disease of the common solid tumours. Consequently, the development of novel anti-cancer therapies is a high priority in cancer medicine. In recent years, a new generation of cancer therapies has emerged, based on a growing understanding of the molecular events that contribute to malignant transformation. A major difference between normal and cancer cells is the ability of cancer cells to multiply in an unrestricted and ungoverned fashion. In this context, there is considerable interest in elucidating the mechanisms that allow this unrestricted proliferation and that ultimately result in immortal cancer cells. It is now clear that the enzyme telomerase confers immortality on cells in most types of cancer. With the cancer cell reliant on telomerase for its survival, telomerase represents an extremely attractive mechanism-based target for the development of new cancer therapeutics.

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Pharmacoproteomic and toxicoproteomic study of the natural product Ebenfuran III in DU-145 prostate cancer cells using iTRAQ with 2D LC and tandem mass spectrometry

Planta Medica ◽

10.1055/s-0028-1083920 ◽

2008 ◽

Vol 74 (09) ◽

Author(s):

M Halabalaki ◽

IT Roumeliotis ◽

E Giannopoulou ◽

X Alexi ◽

L Meijer ◽

...

Keyword(s):

Prostate Cancer ◽

Mass Spectrometry ◽

Tandem Mass Spectrometry ◽

Cancer Cells ◽

Natural Product ◽

Tandem Mass ◽

Prostate Cancer Cells

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In Search of Novel Cancer Therapeutics: Assessing the NCI Natural Product Library against Ten Anti-Apoptotic Protein Targets

Planta Medica ◽

10.1055/s-0033-1348587 ◽

2013 ◽

Vol 79 (10) ◽

Author(s):

DB Divlianska ◽

AE Wright ◽

S Francis ◽

MA Walters ◽

CE Salomon ◽

...

Keyword(s):

Natural Product ◽

Cancer Therapeutics ◽

Protein Targets ◽

Apoptotic Protein ◽

Natural Product Library

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Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

10.26434/chemrxiv.6103607.v1 ◽

2018 ◽

Author(s):

Jonathan J. Mills ◽

Kaylib R. Robinson ◽

Troy E. Zehnder ◽

Joshua G. Pierce

Keyword(s):

Natural Products ◽

Natural Product ◽

Mechanism Of Action ◽

Marine Natural Products ◽

Biological Evaluation ◽

Lead Compounds ◽

Follow Up Studies ◽

Initial Resistance ◽

Synthesis And Biological Evaluation

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

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