Synthesis of structurally simplified analogues of aplidinone A, a pro-apoptotic marine thiazinoquinone

Aiello, Anna; Fattorusso, Ernesto; Luciano, Paolo; Menna, Marialuisa; Calzado, Marco A.; Muñóz, Eduardo; Bonadies, F.; Guiso, Marcella; Sanasi, Maria Filomena; Cocco, Gianfranco; Nicoletti, Rosario

doi:10.1016/j.bmc.2009.11.063

Cited by 20 publications

(29 citation statements)

References 31 publications

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“…To reach these challenging aims, the identification and selection of new lead compounds constitutes a crucial point. 14 Previously, we have recognized the condensation reaction of hypotaurine with quinones, using the known conjugate addition reaction of amines and sulfinic acids, as a simple and versatile way to synthesize a series of analogues of a marine natural thiazinoquinone, aplidinone A (9), isolated from the Mediterranean ascidian Aplidium conicum 16,17 (compounds 11-16, Figure 2). The use of medicinal plants for the treatment of parasitic diseases is well known and documented since ancient times, 7,8 but the screening of biologically active natural compounds with potential antimalarial activity, isolated from both terrestrial 8,9 and marine 10,11 organisms, is still now of considerable interest.…”

Section: Introductionmentioning

confidence: 99%

Marine inspired antiplasmodial thiazinoquinones: synthesis, computational studies and electrochemical assays

et al. 2015

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In the search for new antimalarials, we used the quinone scaffold of marine secondary metabolites as a chemical starting point to synthesize new thiazinoquinone compounds. Most of synthetic derivatives have shown a significant pharmacological activity and some structural requirements, critical for both the antiplasmodial effect and cytotoxicity, have been evidenced. The redox properties of the prepared compounds have been investigated by computational studies and electrochemical assays, which indicated that a higher antiplasmodial activity of some thiazinoquinones is related to their greater ability to form the semiquinone species and strongly interact with free Fe(III)-protoporphyrin IX

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Section: Introductionmentioning

confidence: 99%

Marine inspired antiplasmodial thiazinoquinones: synthesis, computational studies and electrochemical assays

et al. 2015

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“…Previous studies by ourselves [16,19] and others [20,21] have found that hypotaurine addition to quinones typically yields a mixture of regio-isomeric thiazine adducts. In the present study, we found that slow addition of a dilute solution of hypotaurine in MeCN/EtOH at room temperature afforded, after filtration and washing, analogues 7a – 7j in yields of 14%, 27%, 57%, 17%, 49%, 57%, 29%, 29%, 26% and 20%, respectively.…”

Section: Resultsmentioning

confidence: 99%

Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents

et al. 2013

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Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC50 3.1 μM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 3.3 μM) while exhibiting low levels of cytotoxicity (L6, IC50 167 μM). A series of C-7 amide and Δ2(3) analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC50 0.62–6.5 μM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ2(3)-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while Δ2(3)-phenethylamide 8e (IC50 0.67 μM, SI 78) exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC50 0.34–0.035 μM) combined with excellent selectivity (SI 560–4000). In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively.

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“…The pro-apoptotic mechanism of thiaplidiaquinones involves the induction of a strong production of intracellular reactive oxygen species (ROS) in the cells, likely due to the inhibition of the plasma membrane NADH-oxidoreductase (PMOR) system, an important target for anticancer drugs, through interference with the coenzyme-Q binding site [41]. In order to validate the structural assignment made for aplidinones by theoretical means a synthetic approach has been undertaken which yielded some synthetic analogs of aplidinone A in which the geranyl chain is replaced by other alkyl chains [44]; these compounds as well as the natural metabolite 63 were subjected to cytotoxicity assays and preliminary structure-activity relationships (SAR) studies. Both aplidinone A and its synthetic analogs were shown to possess interesting cytotoxic effects; SAR studies revealed that cytotoxic activity depends on the nature and the length of side chain linked to the benzoquinone ring and, mainly, on its position respect to the dioxothiazine ring.…”

Section: Meroterpenes From Ascidiansmentioning

confidence: 99%

“…Both aplidinone A and its synthetic analogs were shown to possess interesting cytotoxic effects; SAR studies revealed that cytotoxic activity depends on the nature and the length of side chain linked to the benzoquinone ring and, mainly, on its position respect to the dioxothiazine ring. The study also evidenced one of the synthetic analogs as a potent cytotoxic and pro-apoptotic agent against several tumor cell lines, which also inhibits the TNFα-induced NF-κB activation in a human leukemia T cell line [44]. …”

Section: Meroterpenes From Ascidiansmentioning

confidence: 99%

Meroterpenes from Marine Invertebrates: Structures, Occurrence, and Ecological Implications

et al. 2013

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Meroterpenes are widely distributed among marine organisms; they are particularly abundant within brown algae, but other important sources include microorganisms and invertebrates. In the present review the structures and bioactivities of meroterpenes from marine invertebrates, mainly sponges and tunicates, are summarized. More than 300 molecules, often complex and with unique skeletons originating from intra- and inter-molecular cyclizations, and/or rearrangements, are illustrated. The reported syntheses are mentioned. The issue of a potential microbial link to their biosynthesis is also shortly outlined.

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Synthesis of structurally simplified analogues of aplidinone A, a pro-apoptotic marine thiazinoquinone

Cited by 20 publications

References 31 publications

Marine inspired antiplasmodial thiazinoquinones: synthesis, computational studies and electrochemical assays

Marine inspired antiplasmodial thiazinoquinones: synthesis, computational studies and electrochemical assays

Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents

Meroterpenes from Marine Invertebrates: Structures, Occurrence, and Ecological Implications

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