Kevin W. Wellington

Understanding cancer and the anticancer activities of naphthoquinones – a review

The non-communicable disease, cancer, is one of the major causes of death across the world and is forecast to increase by 75% to reach close to 25 million cases over the next two decades. Radiotherapy and surgical approaches have been unsuccessful in controlling the incidence of most cancers. The development of chemotherapeutic strategies involving novel small molecule antitumour agents has therefore been the focus area of cancer chemotherapy for several decades as another strategy to combat and control the incidence of cancer. Many natural products as well as several synthetic drugs have a naphthoquinone chromophore. The anticancer activities of naphthoquinones have been the focus of much research to discover novel anticancer agents. The naturally occurring 1,2-naphthoquinone-based compound, β-lapachone (ARQ 761), is currently being assessed for its anti-tumour activity against advanced solid tumours. This review describes the most recent applications of naphthoquinones and their derivatives in cancer drug discovery. The biology relevant to the design of novel naphthoquinone anticancer agents is also discussed. Furthermore, the discussion of the biology will contribute to understanding cancer as well as the applications of naphthoquinones as anticancer agents.

A review: synthesis of aryl C-glycosides via the heck coupling reaction.

In this article, we focus on the synthesis of aryl C-glycosides via Heck coupling. It is organized based on the type of structures used in the assembly of the C-glycosides (also called C-nucleosides) with the following subsections: pyrimidine C-nucleosides, purine C-nucleosides, and monocyclic, bicyclic, and tetracyclic C-nucleosides. The reagents and conditions used for conducting the Heck coupling reactions are discussed. The subsequent conversion of the Heck products to the corresponding target molecules and the application of the target molecules are also described.

A laccase-catalysed one-pot synthesis of aminonaphthoquinones and their anticancer activity

Nuclear monoamination of a 1,4-naphthohydroquinone with primary aromatic amines was catalysed by the commercial laccase, Novozym 51003, from Novozymes to afford aminonaphthoquinones. The synthesis was accomplished by reacting a mixture of the primary amine and 1,4-naphthohydroquinone in succinate-lactate buffer and a co-solvent, dimethylformamide, under mild reaction conditions in a vessel open to air at pH 4.5 and pH 6.0. Anticancer screening showed that the aminonaphthoquinones exhibited potent cytostatic effects particularly against the UACC62 (melanoma) cancer cell line (GI(50)=3.98-7.54 μM). One compound exhibited potent cytostatic effects against both the TK10 (renal) and the UACC62 (melanoma) cancer cell line. The cytostatic effects of this compound (GI(50)=8.38 μM) against the TK10 cell line was almost as good as that of the anticancer agent, etoposide (GI(50)=7.19μM). Two compounds exhibited potent cytostatic effects against both the UACC62 (melanoma) and the MCF7 (breast) cancer cell lines. The total growth inhibition (TGI) of most of the compounds was better than that of etoposide against the UACC62 cell line. Three compounds (TGI=7.17-7.94 μM) exhibited potent cytostatic effects against the UACC62 cell line which was 7 to 8-fold better than that of etoposide (TGI=52.71 μM). The results are encouraging for further study of the aminonaphthoquinones for potential application in anticancer therapy.

Diamination by N-coupling using a commercial laccase

Nuclear diamination of p-hydrobenzoquinones with aromatic and aliphatic primary amines was catalysed by an immobilised commercial laccase, Denilite II Base, from Novozymes. The amine and the p-hydrobenzoquinone was reacted under mild conditions (at room temperature and at 35 degrees C) in a reaction vessel open to air in the presence of laccase and a co-solvent to afford, exclusively, the diaminated p-benzoquinone. These compounds may have potential antiallergic, antibiotic, anticancer, antifungal, antiviral and/or 5-lipoxygenase inhibiting activity.

A one-pot synthesis of 1,4-naphthoquinone-2,3-bis-sulfides catalysed by a commercial laccase

Oxidative C–S bond formation with aryl and alkyl thiols was catalysed under mild conditions in a reaction vessel open to air at pH 4.5 and 7.15 in the presence of a commercial laccase (Novozym 51003) and a co-solvent (DMF) to afford 1,4-naphthoquinone-2,3-bis-sulfides. The synthesis of 1,4-naphthoquinone-2,3-bis-sulfides from two different 1,4-naphthohydroquinone substrates was investigated with regard to pH and number of equivalents of the thiol.

One-Pot Laccase-Catalysed Synthesis of 5,6-Dihydroxylated Benzo[b]furans and Catechol Derivatives, and Their Anticancer Activity

A commercial laccase, Suberase® from Novozymes, was used to catalyse the synthesis of 5,6‐dihydroxylated benzo[b]furans and catechol derivatives. The yields were, in some cases, similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The synthesised derivatives were screened against renal (TK10), melanoma (UACC62), breast (MCF7) and cervical (HeLa) cancer cell lines. GI50, TGI and LC50 are reported for the first time. Anticancer screening showed that the cytostatic effects of the 5,6‐dihydroxylated benzo[b]furans were most effective against the melanoma (UACC62) cancer cell line with several compounds exhibiting potent growth inhibitory activities (GI50 = 0.77–9.76 µM), of which two compounds had better activity than the anticancer agent etoposide (GI50 = 0.89 µM). One compound exhibited potent activity (GI50 = 9.73 µM) against the renal (TK10) cancer cell line and two exhibited potent activity (GI50 = 8.79 and 9.30 µM) against the breast (MCF7) cancer cell line. These results encourage further studies of the 5,6‐dihydroxylated benzo[b]furans for their potential application in anticancer therapy.

A Convenient Synthesis of N,N′-dibenzyl-2,4-diaminopyrimidine-2′-deoxyribonucleoside and 1-Methyl-2′-Deoxypseudoisocytidine

The syntheses of N,N′-dibenzyl-2,4-diaminopyrimidine-2′-deoxyribonucleoside and 1-methyl-2′-deoxypseudoisocytidine via Heck coupling are described. A survey of the attempts to use the Heck coupling to synthesize N,N′-dibenzyl-2,4-diaminopyrimidine-2′-deoxyribonucleoside is provided, indicating a remarkable diversity in outcome depending on the specific heterocyclic partner used.

Acaricidal activity of the organic extracts of thirteen South African plants against Rhipicephalus (Boophilus) decoloratus (Acari: Ixodidae).

The African blue tick, Rhipicephalus (Boophilus) decoloratus, is a common tick species found in South Africa and affects cattle production as well as vectoring pathogens in regions of Africa and Asia. In an attempt to develop a non-toxic, lower cost and environmentally friendly tick control method, twenty-six plant extracts were prepared from thirteen plant species using 99.5% acetone and 99% ethanol. The adapted Shaw Larval Immersion Test (SLIT) was used to test the efficacy of the extracts. A 1% solution of each of the plant extracts was prepared for efficacy testing and the ethanol extracts were found to have better acaricidal activity than the acetone extracts. The ethanol extract from the leaves and flowers of Calpurnia aurea had the best activity [corrected mortality (CM)=82.9%] which was followed by the stem extract of Cissus quadrangularis (CM=80.4%). The plant species were screened against Vero cells and were found to have low toxicity. From this study it is apparent that there is potential for the development of botanicals as natural acaricides against R. (B.) decoloratus.

Further studies on South African plants: Acaricidal activity of organic plant extracts against Rhipicephalus (Boophilus) microplus (Acari: Ixodidae)

The goal of our research is to develop a lower cost eco-friendly tick control method because acaricides that are commonly used to control ticks are often toxic, harmful to the environment or too expensive for resource-limited farmers. Acetone and ethanol extracts were prepared and their acaricidal activities determined against the southern cattle tick, Rhipicephalus (Boophilus) microplus. A 1% solution of each of the plant extracts was prepared for efficacy testing using the adapted Shaw Larval Immersion Test (SLIT). The acetone stem extract from Cissus quadrangularis (Vitaceae) and the ethanol leaf and flower extract from Calpurnia aurea (Fabaceae) had potent activity like that of the commercial acaricide, chlorfenvinphos [corrected mortality (CM)=100.0%]. The ethanol extracts of the stem of C. quadrangularis (CM=98.9%) and that of the roots, leaves and fruit of Senna italica subsp arachoides (CM=96.7%) also had good acaricidal activity. There is potential for the development of botanicals as natural acaricides against R. (B.) microplus that can be used commercially to protect animals against tick infestation. Further studies to isolate the acaricidal active compounds and to determine the environmental fate, species toxicity and skin toxicity of these plants species are, however, required before they can be considered as a treatment against ticks.

A one-pot laccase-catalysed synthesis of coumestan derivatives and their anticancer activity.

Suberase®, a commercial laccase from Novozymes, was used to catalyse the synthesis of coumestans. The yields, in some cases, were similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The compounds were screened against renal TK10, melanoma UACC62 and breast MCF7 cancer cell-lines and the GI50, TGI and LC50 values determined. Anticancer screening showed that the cytostatic effects of the coumestans were most effective against the melanoma UACC62 and breast MCF7 cancer cell-lines exhibiting potent activities, GI50=5.35 and 7.96μM respectively. Moderate activity was obtained against the renal TK10 cancer cell-line. The total growth inhibition, based on the TGI values, of several of the compounds was better than that of etoposide against the melanoma UACC62 and the breast MCF7 cancer cell lines. Several compounds, based on the LC50 values, were also more lethal than etoposide against the same cancer cell lines. The SAR for the coumestans is similar against the melanoma UACC62 and breast MCF7 cell lines. The compound having potent activity against both breast MCF7 and melanoma UACC62 cell lines has a methyl group on the benzene ring (ring A) as well as on the catechol ring (ring B). Anticancer activity decreases when methoxy and halogen substituents are inserted on rings A and B.