Synthesis of Plastoquinone Analogs and Inhibition of Photosynthetic and Mammalian Enzyme Systems

Abstract

New 5-hydroxy-and 5-chloro-6-alkyl-1,4-benzoquinones with one or two methyl groups on the nucleus were synthesized as potential antimetabolites of plastoquinones for biological research on photosynthetic and mammalian enzyme systems; the primary emphasis was on photosynthesis.2,3-Dimethyl-5 -hydroxy -6 -phytyl -1,4 -benzoquinone completely inhibited in chloroplasts the water-dependent electron transport, but photosystem I was insensitive to this analog. The data are consistent with the interpretation that this analog inhibits electron transport in the chain prior to the site of electron donation from the ascorbate-dichlorophenolindophenol couple. Concentrations of 70 MM and 120 ,M of this analog caused about 50 and 100% inhibition, respectively, of cyclic photophosphorylation.2,3-Dimethyl-5-hydroxy-6-phytyl-1 ,4-benzoquinone is a new type of inhibitor of photosynthetic electron transport that specifically inhibits the rate-limiting step between photosystems I and II. Structurally related analogs caused inhibitions in the range of 50-100% in chloroplasts.These analogs showed marginal inhibition in mitochondrial coenzyme Qjo-oxidase systems from beef heart.Plastoquinone-9 (Plastoquinone-9,I), a compound foundpredominately in the chloroplasts of higher plants, is a naturally occurring benzoquinone with an isoprenoid side chain. Its structure was determined (1), and it was synthesized (2). It was proposed that it has an important role in the electron transport system of photosynthesis that is analogous to that of coenzyme Q (II) in mitochondria (3) by acting as an oxidation-reduction carrier in the electron transport system associated with the transformation of light into chemical energy (ATP) and the utilization of the hydrogen of water as a source of reducing power (NADPH2). Data from several experimental approaches indicate that plastoquinone does function in the electron transport system of chloroplasts. The data stem from extraction-restoration studies, spectrophotometric and chemical determination of redox changes, correlation with metabolic function, and changes in electron transport in mutants, as well as its universal distribution in all oxygen-producing photosynthetic organisms (3).To study relationships between structure and activity in respiration, Redfearn and Whittaker (4) evaluated the inhibition of succinoxidase from a heart muscle preparation by both coenzyme Q and l)lastoquinone analogs. They found that inhibitory quinones have at least one unsubstituted position in the nucleus, that the nature of the substituent ortho to the free position was important, and that the inhibitory effect disappeared in the presence of sulfhydryl compounds. Quinones with one unsubstituted position in the nucleus are known to react by a 1,4-addition with molecules containing a thiol group. This reaction might be involved in the mechanism of inhibition by the compounds studied by these investigators.Catlin et al. (5)

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

“…Regarding uses of important drugs for the treatment of cancer, mitomycin C, mitoxantrone, and doxorubicin draw attention and contain the 1,4-quinone moiety ( Figure 2 ). After realizing the prominent anticancer activity of those structures, we created more using nature as a model, namely plastoquinones ( PQ ) discovered by Barr for electron transfer in photosynthesis in 1946 [ 24 ] containing both 2,3-dimethyl-1,4-benzoquinone structure and a side chain of nine isoprenyl group as PQ-A or PQ-9 [ 25 ] or shorter side chain such as PQ-3 with three isoprenyl side units, as shown in Figure 3 [ 26 ]. Studying common pharmacophoric features of PQ analogs has revealed that the presence of three main features, as shown in Figure 3 , are important.…”

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

“…Drugs such as mitomycin C, mitoxantrone, and doxorubicin and some of the biologically active synthetic molecules contain 1,4-quinone moiety. Our strategy was inspired by a natural 2,3-dimethyl-1,4-benzoquinone structure with a side chain of nine isoprenyl groups named PQ-A or PQ-9 [ 30 ], as well as those containing shorter side chains such as PQ-3, having three isoprenyl side units as shown in Figure 1 [ 31 ]. In the past three years, we have published the syntheses and extensive exploration of a broad range of various PQ analogs to elucidate their antiproliferative and/or antibiotic profiles using 2,3-di-methylhydroquinone as a precursor [ 21 , 23 , 26 , 28 , 32 , 33 ].…”