Design of Oleanolic Acid-Based Hybrid Compounds as Potential Pharmaceutical Scaffolds

Background: Infectious diseases as well as cancer are the leading causes of death worldwide. Drug resistance usually results in their treatment requiring a combination of two or more drugs. Objective: Oleanolic-based hybrid compounds were prepared via esterification and characterized using FTIR, NMR, and LC-MS. In vitro antibacterial and in vitro cytotoxicity studies were performed. Method: Oleanolic acid was hybridized with selected known pharmaceutical scaffolds via the carboxylic acid functionality to develop therapeutics with increased biological activity. Antibacterial activity was determined using the micro-dilution assay against selected Gram-positive and Gram-negative bacteria and cytotoxicity using the sulforhodamine B assay. Results: Compound 8 displayed potent antibacterial effect against five strains of bacteria such as Bacillus subtilis, Staphylococcus aureus, Proteus vulgaris, Klebsiella oxytoca, and Escherichia coli with MIC values of 1.25, 0.078, 0.078, 1.25, 1.25 mg/mL when compared to the control, oleanolic acid (MIC = 2.5 mg/mL). Furthermore, in vitro cytotoxicity, as determined using the SRB assay, against selected cancer cells revealed that compound 7 was the most cytotoxic to MDA, DU145, and MCF-7 cell lines with IC50 values of 69.87±1.04, 73.2±1.08, and 85.27±1.02 µg/mL, respectively, than oleanolic acid with an IC50 ˃200 µg/mL. Conclusion: Hybridization of oleanolic acids was successful, and further development of these potential antibacterial compounds with reduced cytotoxicity is warranted.

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In vitro cytotoxicity studies on Carissa congesta, Polyalthia longifolia, and Benincasa hispida extracts by Sulforhodamine B assay method

International Journal of Green Pharmacy ◽

10.4103/0973-8258.161232 ◽

2015 ◽

Vol 9 (3) ◽

pp. 157 ◽

Cited By ~ 2

Author(s):

GauravMahesh Doshi ◽

HemantD Une

Keyword(s):

In Vitro Cytotoxicity ◽

Assay Method ◽

Sulforhodamine B ◽

Cytotoxicity Studies ◽

Sulforhodamine B Assay ◽

Benincasa Hispida ◽

Polyalthia Longifolia

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Tris-(2-pyridyl)-pyrazolyl Borate Zinc(II) Complexes: Synthesis, DNA/Protein Binding and In Vitro Cytotoxicity Studies

Molecules ◽

10.3390/molecules26237341 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7341

Author(s):

Manmath Narwane ◽

Dorothy Priyanka Dorairaj ◽

Yu-Lun Chang ◽

Ramasamy Karvembu ◽

Yu-Han Huang ◽

...

Keyword(s):

Anticancer Agents ◽

Binding Mode ◽

In Vitro Cytotoxicity ◽

Visible Absorption ◽

Cytotoxicity Studies ◽

Ic50 Values ◽

State Behaviour ◽

Analytical Tools ◽

Ct Dna

Zn(II) complexes bearing tris[3-(2-pyridyl)-pyrazolyl] borate (Tppy) ligand (1–3) was synthesized and examined by spectroscopic and analytical tools. Mononuclear [TppyZnCl] (1) has a Zn(II) centre with one arm (pyrazolyl-pyridyl) dangling outside the coordination sphere which is a novel finding in TppyZn(II) chemistry. In complex [TppyZn(H2O)][BF4] (2) hydrogen bonding interaction of aqua moiety stabilizes the dangling arm. In addition, solution state behaviour of complex 1 confirms the tridentate binding mode and reactivity studies show the exogenous axial substituents used to form the [TppyZnN3] (3). The complexes (1–3) were tested for their ability to bind with Calf thymus (CT) DNA and Bovine serum albumin (BSA) wherein they revealed to exhibit good binding constant values with both the biomolecules in the order of 104–105 M−1. The intercalative binding mode with CT DNA was confirmed from the UV-Visible absorption, viscosity, and ethidium bromide (EB) DNA displacement studies. Further, the complexes were tested for in vitro cytotoxic ability on four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, MDA-MB-468, HCC1937, and Hs 578T). All three complexes (1–3) exhibited good IC50 values (6.81 to 16.87 μM for 24 h as seen from the MTS assay) results which indicated that these complexes were found to be potential anticancer agents against the TNBC cells.

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Synthesis, antibacterial, and cytotoxicity evaluation of oleanolic acid-4-aminoquinoline based hybrid compounds

Recent Patents on Anti-Infective Drug Discovery ◽

10.2174/1574891x16666210210165547 ◽

2021 ◽

Vol 16 ◽

Author(s):

Vuyolwethu Khwaza ◽

Opeoluwa O. Oyedeji ◽

Blessing A. Aderibigbe ◽

Eric Morifi ◽

Y.T. Fonkui ◽

...

Keyword(s):

Drug Resistance ◽

Cell Lines ◽

Oleanolic Acid ◽

Cancer Cell ◽

Antimicrobial Agents ◽

Klebsiella Oxytoca ◽

Cancer Cell Lines ◽

Hybrid Compounds ◽

Microbial Infections

Aim: To prepare a class of oleanolic-based compounds. Background: Conventional drugs used to treat infectious diseases suffer from limitations such as drug toxicity and drug resistance. The resistance of microbes to antimicrobial agents is a significant challenge in treating microbial infections. Combining two or more drugs with different modes of action to treat microbial infections results in a delay in developing drug resistance by the microbes. However, it is challenging to select the appropriate choice of drugs for combination therapy due to the differences in stability and pharmacokinetic proﬁle of the drugs.Therefore, developing hybrid compounds using the existing drugs is a promising approach to design effective antimicrobial agents. Objectives: To prepare oleanolic-based hybrid compounds followed by characterization, in vitro antibacterial, and cytotoxicity evaluation. Methods:: Oleanolic acid-4-aminoquinoline-based hybrid compounds weresynthesized via esterification and amidation. The compounds werecharacterized using FTIR, NMR, and UHPLC-HRMS. Oleanolic acid was isolated from the flower buds of Syszygium aromaticum (L.) Merr. &.Perry, a specie from Kingdom Plantae, order Mytales in Myrtaceae family. Their antibacterial and cytotoxicity activity was determined against selected strains of bacteria assessed using the microdilution assay and sulforhodamine B assay against selected cancer cell lines. Results: The synthesized hybrid compounds exhibited significant antibacterial activity against the Gram-positive bacteria Enterococcus faecalis (ATCC13047), Bacillus subtilis (ATCC19659), Staphylococcus aureus as well as Gram-negative bacteria,Klebsiella oxytoca (ATCC8724), Escherischia coli (ATCC25922), and Proteus vulgaris (ATCC6380)with minimum inhibitory concentrations of 1.25 mg/mLcompared to oleanolic acid (2.5 mg/mL). Compounds 13 and 14 displayed significant cytotoxic effectsin vitro against the cancer cell lines (MCF-7 and DU 145) compared to the oleanolic acid (IC50 ˃ 200 µM). Conclusion: The present study revealed that the modification of C28 of OA enhanced its biological properties.

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Synthesis and in vitro Cytotoxicity Studies of Certain Novel Heterocycles Derived from Bis 1, 2, 4-Triazoles and their DNA Damage Studies

Medicinal Chemistry ◽

10.2174/1573406411309080008 ◽

2013 ◽

Vol 9 (8) ◽

pp. 1063-1072

Author(s):

Madhusudan Purohit ◽

Chandrashekhar Mangannavar ◽

Mayur Yergeri

Keyword(s):

Dna Damage ◽

In Vitro Cytotoxicity ◽

Cytotoxicity Studies

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The Effect of Phase Transition Temperature on Therapeutic Efficacy of Liposomal Bortezomib

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200101150640 ◽

2020 ◽

Vol 20 (6) ◽

pp. 700-708

Author(s):

Mitra Korani ◽

Sara Nikoofal-Sahlabadi ◽

Amin R. Nikpoor ◽

Solmaz Ghaffari ◽

Hossein Attar ◽

...

Keyword(s):

Side Effects ◽

Cell Line ◽

Therapeutic Efficacy ◽

Drug Loading ◽

Particle Diameter ◽

In Vitro Cytotoxicity ◽

Liposomal Formulations ◽

Cytotoxicity Studies ◽

Anti Tumor Activity

Aims: Here, three liposomal formulations of DPPC/DPPG/Chol/DSPE-mPEG2000 (F1), DPPC/DPPG/Chol (F2) and HSPC/DPPG/Chol/DSPE-mPEG2000 (F3) encapsulating BTZ were prepared and characterized in terms of their size, surface charge, drug loading, and release profile. Mannitol was used as a trapping agent to entrap the BTZ inside the liposomal core. The cytotoxicity and anti-tumor activity of formulations were investigated in vitro and in vivo in mice bearing tumor. Background: Bortezomib (BTZ) is an FDA approved proteasome inhibitor for the treatment of mantle cell lymphoma and multiple myeloma. The low solubility of BTZ has been responsible for the several side effects and low therapeutic efficacy of the drug. Encapsulating BTZ in a nano drug delivery system; helps overcome such issues. Among NDDSs, liposomes are promising diagnostic and therapeutic delivery vehicles in cancer treatment. Objective: Evaluating anti-tumor activity of bortezomib liposomal formulations. Methods: Data prompted us to design and develop three different liposomal formulations of BTZ based on Tm parameter, which determines liposomal stiffness. DPPC (Tm 41°C) and HSPC (Tm 55°C) lipids were chosen as variables associated with liposome rigidity. In vitro cytotoxicity assay was then carried out for the three designed liposomal formulations on C26 and B16F0, which are the colon and melanoma cancer mouse-cell lines, respectively. NIH 3T3 mouse embryonic fibroblast cell line was also used as a normal cell line. The therapeutic efficacy of these formulations was further assessed in mice tumor models. Result: MBTZ were successfully encapsulated into all the three liposomal formulations with a high entrapment efficacy of 60, 64, and 84% for F1, F2, and F3, respectively. The findings showed that liposomes mean particle diameter ranged from 103.4 to 146.8nm. In vitro cytotoxicity studies showed that liposomal-BTZ formulations had higher IC50 value in comparison to free BTZ. F2-liposomes with DPPC, having lower Tm of 41°C, showed much higher anti-tumor efficacy in mice models of C26 and B16F0 tumors compared to F3-HSPC liposomes with a Tm of 55°C. F2 formulation also enhanced mice survival compared with untreated groups, either in BALB/c or in C57BL/6 mice. Conclusion: Our findings indicated that F2-DPPC-liposomal formulations prepared with Tm close to body temperature seem to be effective in reducing the side effects and increasing the therapeutic efficacy of BTZ and merits further investigation.

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Recent Advances in Curcumin Nanocarriers for the Treatment of Different Types of Cancer with Special Emphasis on In Vitro Cytotoxicity and Cellular Uptake Studies

Nanoscience &Nanotechnology-Asia ◽

10.2174/2210681209666190417144126 ◽

2020 ◽

Vol 10 (5) ◽

pp. 577-590

Author(s):

Jai B. Sharma ◽

Shailendra Bhatt ◽

Asmita Sharma ◽

Manish Kumar

Keyword(s):

Cancer Cells ◽

Cellular Uptake ◽

Anticancer Agents ◽

Targeted Delivery ◽

In Vitro Cytotoxicity ◽

Curcumin Nanoparticles ◽

Cytotoxicity Studies ◽

Delivery Technique ◽

Different Types

Background: The potential use of nanocarriers is being explored rapidly for the targeted delivery of anticancer agents. Curcumin is a natural polyphenolic compound obtained from rhizomes of turmeric, belongs to family Zingiberaceae. It possesses chemopreventive and chemotherapeutic activity with low toxicity in almost all types of cancer. The low solubility and bioavailability of curcumin make it unable to use for the clinical purpose. The necessity of an effective strategy to overcome the limitations of curcumin is responsible for the development of its nanocarriers. Objective: This study is aimed to review the role of curcumin nanocarriers for the treatment of cancer with special emphasis on cellular uptake and in vitro cytotoxicity studies. In addition to this, the effect of various ligand conjugated curcumin nanoparticles on different types of cancer was also studied. Methods: A systematic review was conducted by extensively surfing the PubMed, science direct and other portals to get the latest update on recent development in nanocarriers of curcumin. Results: The current data from recent studies showed that nanocarriers of curcumin resulted in the targeted delivery, higher efficacy, enhanced bioavailability and lower toxicity. The curcumin nanoparticles showed significant inhibitory effects on cancer cells as compared to free curcumin. Conclusion: It can be concluded that bioavailability of curcumin and its cytotoxic effect to cancer cells can be enhanced by the development of curcumin based nanocarriers and it was found to be a potential drug delivery technique for the treatment of cancer.

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Novel Hybrid Compounds Containing Benzofuroxan and Aminothiazole Scaffolds: Synthesis and Evaluation of Their Anticancer Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22147497 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7497

Author(s):

Elena Chugunova ◽

Gabriele Micheletti ◽

Dario Telese ◽

Carla Boga ◽

Daut Islamov ◽

...

Keyword(s):

Anticancer Agents ◽

Normal Liver ◽

Mitochondrial Pathway ◽

Reaction Pathways ◽

Aromatic Nucleophilic Substitution ◽

X Ray ◽

Hybrid Compounds ◽

Aromatic Nucleophilic Substitution Reaction ◽

Further Development

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Тamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents.

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New Antiproliferative Triflavanone from Thymelaea hirsuta—Isolation, Structure Elucidation and Molecular Docking Studies

Molecules ◽

10.3390/molecules26030739 ◽

2021 ◽

Vol 26 (3) ◽

pp. 739

Author(s):

Sameh S. Elhady ◽

Reda F. A. Abdelhameed ◽

Mayada M. El-Ayouty ◽

Amany K. Ibrahim ◽

Eman S. Habib ◽

...

Keyword(s):

Molecular Docking ◽

Liver Tumors ◽

Fold Increase ◽

In Vitro Cytotoxicity ◽

Mitogen Activated Protein Kinase ◽

Wild Plant ◽

Cytotoxic Activities ◽

Ic50 Values ◽

Thymelaea Hirsuta

In this study isolates from Thymelaea hirsuta, a wild plant from the Sinai Peninsula of Egypt, were identified and their selective cytotoxicity levels were evaluated. Phytochemical examination of the ethyl acetate (EtOAc) fraction of the methanolic (MeOH) extract of the plant led to the isolation of a new triflavanone compound (1), in addition to the isolation of nine previously reported compounds. These included five dicoumarinyl ethers found in Thymelaea: daphnoretin methyl ether (2), rutamontine (3), neodaphnoretin (4), acetyldaphnoretin (5), and edgeworthin (6); two flavonoids: genkwanin (7) and trans-tiliroside (8); p-hydroxy benzoic acid (9) and β sitosterol glucoside (10). Eight of the isolated compounds were tested for in vitro cytotoxicity against Vero and HepG2 cell lines using a sulforhodamine-B (SRB) assay. Compounds 1, 2 and 5 exhibited remarkable cytotoxic activities against HepG2 cells, with IC50 values of 8.6, 12.3 and 9.4 μM, respectively, yet these compounds exhibited non-toxic activities against the Vero cells. Additionally, compound 1 further exhibited promising cytotoxic activity against both MCF-7 and HCT-116 cells, with IC50 values of 4.26 and 9.6 μM, respectively. Compound 1 significantly stimulated apoptotic breast cancer cell death, resulting in a 14.97-fold increase and arresting 40.57% of the cell population at the Pre-G1 stage of the cell cycle. Finally, its apoptosis-inducing activity was further validated through activation of BAX and caspase-9, and inhibition of BCL2 levels. In silico molecular docking experiments revealed a good binding mode profile of the isolates towards Ras activation/pathway mitogen-activated protein kinase (Ras/MAPK); a common molecular pathway in the development and progression of liver tumors.

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