The synthesis, isolation and evaluation of novel anticancer and antibacterial therapeutics derived from natural products

Omonga, N 2020, The synthesis, isolation and evaluation of novel anticancer and antibacterial therapeutics derived from natural products , PhD thesis, University of Salford.

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This study focused on isolation, synthesis, development and evaluation of novel antimicrobial and anticancer agents from natural product. Natural products have found lead applications in the pharmaceutical industry as sources of chemotherapeutics against cancers and infectious diseases. This investigation focussed on isolating sesquiterpene lactones from natural products, and synthesis of flavonoid based anticancer and antimicrobial agents from the flavonoid – chrysin because sesquiterpene lactones and flavonoids are potent anticancer and antimicrobial agents. In addition to the sesquiterpene lactones – alantolactone (D1) and isoalantolactone (D2), this is the first time costunolide (D3) has been isolated from Inula helenium. A series of 8-novel and 10 known Chrysin-derivatives were also synthesised via microwave-assisted O-alkylation of chrysin and other synthetic methods, and their antimicrobial and anticancer activities investigated. Twenty compounds were screened against eight bacteria and one fungus - Candida albicans using Gentamycin and Fluconazole as standard drugs for antibacterial and antifungal studies. 4-((5-Hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)butyl acetate (C1), 7-((3,5-dimethylbenzyl)oxy)-5-hydroxy-2-phenyl-4H-chromen-4-one (C2) and 7-(2,4-Dinitrophenoxy)-5-hydroxy-3-phenyl-4H-chromen-4-one (C3) indicated bactericidal inhibition against a broad spectrum of bacteria and Candida albicans; Staphylococcus aureus, Escherichia coli, Bacillus cereus and Enterococcus faecalis were the most susceptible bacteria to inhibition by these compounds. MIC of C1 against these microorganisms was 25, 50, 50 and 50 µg / mL, C2: 50, 100, 100 and 100 µg / mL, C3: 12.5, 12.5, 25.0 and 50 µg / mL. MIC values indicated by these compounds were better than those indicated by chrysin and were comparable to those showed by the standard drug – Gentamycin. C1 and C3 also inhibited the growth of the drug-resistant bacteria MRSA at doses of 65 and 100 µg / mL respectively. Chrysin derivatives also inhibited the growth of extended spectrum beta lactamase (ESBL) bacteria – E. coli, K. pneumoniae and P. aeruginosa. C1 and C3 also showed superior antifungal activity against the pathogenic fungus – Candida albicans at MIC values of 50 µg / mL respectively compared to the standard antifungal drug – Fluconazole (MIC 125 µg / mL). 7-O-bromochrysin and 7-O-alkylchrysin derivatives of chrysin showed weak antimicrobial activities (MIC ≥ 125 µg / mL) against all bacteria and fungus tested. D1, D2 and D3 also inhibited the growth of S. aureus and B. cereus at MIC values ≤ 125 µg / mL. The best antimicrobial agent synthesised were C1 and C3. The antiproliferative activities of D1, D2 and D3 were also investigated in hypoxia and normoxia (under hypoglycaemic and hyperglycaemic conditions). In hypoxia D1, D2 and D3 elicited a 10 to 55-fold significant antiproliferative activity against leukaemia cell line (K562) in hypoglycaemic conditions with cytotoxicity (IC50 values) 0.58, 0.66 and 3.07 µM compared to the antiproliferative activity indicated in hyperglycaemic condition (IC50 values – 0.80, 1.18 and 4.77 µM) respectively. In normoxia (normal oxygen concentration), the IC50 values in hypoglycaemia were 1.80, 1.90 and 6.72 µM for D1, D2 and D3. The IC50 values in hyperglycaemia were 2.60, 3.29 and 7.15 µM for D1, D2 and D3 respectively. The antiproliferative activities indicated by D1, D2 and D3 under the conditions stated above were better than those indicated by the positive control – Chlorpromazine hydrochloride (CPZ) with IC50 values 32.88, 27.05, 9.36 and 16.21 µM respectively. D1, D2 and D3 were selectively cytotoxic against cancer cell lines but not the normal cell line – BEAS-2B. Anticancer activities against colorectal cancer cell lines (HCT 116 and Caco-2) indicated by C1, C2 and C3 (IC50 ≤ 2.0 µM for HCT 116, and IC50 ≤ 6.0 µM for Caco-2 cell line), were better than those indicated by chrysin and the positive control drug – (CPZ) – IC50 4.07 and 5.9 µM respectively, and IC50 4.84 µM (chrysin) and 5.17 µM (CPZ) for Caco-2 cell line. C1, C2 and C3 also elicited better anticancer activities against leukaemia (K562) at concentrations of 7.27 µM, 5.58 µM and 8.69 µM; and mesothelioma (Mero-14) cell lines at concentrations of 7.65 µM, 26.31 µM and 8.71 µM respectively, compared to chrysin (IC50 13.13 µM for K562 cell line and 45.99 µM for Mero-14 cell line) and CPZ (IC50 7.38 µM for K562 cell line and 13.42 µM for Mero-14 cell line). Similarly, C1 and C2 also elicited significant cytotoxic inhibition against the triple-negative breast cancer cell line – MDA-MB 468 at IC50 values 7.49 and 16.59 µM compared to chrysin. Anticancer activities elicited by long-chain 7-O-alkylchrysin derivatives (C10, C11 and C12) against HCT 116 cancer cells (IC50 16.4, 17.5 and 18.9 µM) was comparable to those indicated by chrysin and CPZ (IC50 5.9 µM). C16 and C17 also elicited good to moderate cytotoxic inhibition against a broad spectrum of the ten cancer cell lines tested. Interestingly, C1, C2 and C3 were selectively cytotoxic against cancer cell lines but not the normal cell line – BEAS-2B. Chrysin was selectively cytotoxic but CPZ killed both cancer and normal cell lines. D1, D2 and D3 also indicated anticancer inhibition against K562 cell lines during hypoxia and normoxia, and during hyperglycaemia and normoglycaemia. Anticancer inhibition during hypoxia and low glucose for D1 and D2 (IC50 ≤ 0.66 µM) was better than the anticancer inhibition elicited in normoxia and low glucose concentrations (IC50 ≤ 1.8 and 1.9 µM respectively). In this study, novel anticancer and antimicrobial agents which elicited better bioactivity and solubilities compared to standard antimicrobial agents (Gentamycin and Fluconazole), anticancer positive control agent (Doxorubicin) and chrysin (the parent compound) have been synthesised. Furthermore, hyperglycaemia in normoxic condition was associated with rapid cell proliferation in contrast to hypoxia in hypoglycaemic condition. Compounds isolated in this study were more cytotoxic under hypoxic conditions. Costunolide was isolated for the first time from Inula helenium. In-vivo cytotoxicity studies of costunolide against leukaemia cell line – K562 in mammalian models is necessary. Some modified chrysin-derivatives also indicated significant cytotoxicity in-vitro. In-vivo cytotoxicity studies using mammalian model is also required. Synthesised chrysin derivatives were selectively cytotoxic against cancer cell lines but were not toxic against normal cell line at IC50 ≤ 100 µM. From the structure–activity point of view, nature and position of the electron withdrawing and electron donating functional groups on the chrysin core might have contributed to the observed antibacterial and anticancer action. The observed anticancer activity of alantolactone, isoalantolactone, costunolide, C1, C2, C3, C6, C8 and C10 and the antimicrobial activity of C1, C2 and C3 makes them an attractive drug candidate than chrysin and shows that substitution at the 7-OH position of chrysin could enhance the bioactivity of chrysin.

Item Type: Thesis (PhD)
Contributors: Hadfield, JA (Supervisor) and (Supervisor)
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Depositing User: NICHOLAS Omonga
Date Deposited: 15 Jun 2020 09:08
Last Modified: 15 Jun 2020 09:08

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