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siccanin (Piadar / siccanin / Tackle)

✓ Approved

Daiichi Sankyo Company Limited · Small Molecule · Small Molecule

What is siccanin?

siccanin is a small molecule developed by Daiichi Sankyo Company Limited. It is approved for therapeutic indications.

Drug Profile

Brand NamesPiadar, siccanin, Tackle
CompanyDaiichi Sankyo Company Limited
Drug ClassSmall Molecule
StatusApproved

Therapeutic Indications

siccanin is developed for 3 unique indications across 2 therapeutic areas.

Therapeutic AreaConditionPhase
InvestigationsDermatologic examination✓ Approved
Infections and infestationsWound infection fungal✓ Approved
Infections and infestationsCandida infection✓ Approved

Related Research Articles

PubMedJournal of the American Chemical Society2026-09-14

Synthesis of Siccanin by Computational Subtarget Selection.

Pop Larisa P LP, Shenvi Ryan A RA

The species-selective SDH inhibitor siccanin presents unique opportunities for therapeutic development but suffers from poor physicochemical properties and challenging chemical problems. Here we report an approach to its synthesis that quickly intercepts its unusually hindered cis-syn-cis drimane core, i.e., its local chemical space. Computation helps rationalize and predict the reactivity, especially conformational preferences, configurational outcomes, and the reactivity of a key O-centered radical.

PubMedNatural product reports2024-11-04

Siccanin-related drimane meroterpenoids: biological activities and synthesis.

Sun Shengxin S, Wang Xia X, Hu Nvdan N, Fu Shiqi S et al.

Covering: 1962 to 2023Drimane (hydro)quinones biosynthetically arise from the combination of drimane-type terpenoids with phenols or equivalents. Since the isolation of siccanin in 1962 (structure identified in 1967), over 200 natural drimane (hydro)quinones have been reported. They are widespread with remarkably diverse architectures and biological functions, which are achieved by varying either the drimane subunit, hydroquinone segment, or the fusion types of drimane and hydroquinone segment both of them. This type of natural products has drawn increasing attention in the discovery of novel pharmaceutical leads. Enormous efforts have been devoted to developing efficient and divergent synthesis approaches to facilitate the SAR study of drimane (hydro)quinones, aiming for more promising functional leads. This review is arranged mainly in terms of scaffold types of drimane (hydro)quinones and further categorized on the basis of biological functions. The mechanisms of action are also briefly discussed. Synthetic methods are categorized according to the strategies forging the Csp2-Csp3 linker between drimane segments and (hydro)quinone subunits.

PubMedPharmaceuticals (Basel, Switzerland)2022-07-28

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III.

Komatsuya Keisuke K, Sakura Takaya T, Shiomi Kazuro K, Ōmura Satoshi S et al.

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite's ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC50 of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC50 = 10.26 μM) and Dd2-ELQ300 strains (EC50 = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.

PubMedToxins2014-03-29

Inhibitory effects of respiration inhibitors on aflatoxin production.

Sakuda Shohei S, Prabowo Diyan Febri DF, Takagi Keiko K, Shiomi Kazuro K et al.

Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control.

PubMedBiological & pharmaceutical bulletin2011-10-04

Screening for microbial metabolites affecting phenotype of Caenorhabditis elegans.

Yamamuro Daisuke D, Uchida Ryuji R, Takahashi Yoko Y, Masuma Rokuro R et al.

Microbial samples, including our library of known microbial compounds (ca. 300) and microbial culture broths (ca. 9000), were screened for small molecules affecting the phenotype of Caenorhabditis elegans. As a result, seven known compounds were found to induce phenotypic abnormality of C. elegans. Staurosporine exhibited morphological defects in the vulva and tail of C. elegans, avermectin B1a exhibited hatching inhibition of starting eggs on day 1 at 25-100 µM and growth inhibition at 0.01-12.5 µM, siccanin and antimycin A inhibited the growth of C. elegans, and fluorouracil inhibited hatching of eggs newly spawned by adult C. elegans. Toromycin induced morphological defects in the intestine. 5-(4-Methoxyphenyl)-oxazole, isolated as a fungal metabolite for the first time, inhibited the hatching of eggs newly spawned by adult C. elegans.

PubMedJournal of biochemistry2009-06-10

Siccanin rediscovered as a species-selective succinate dehydrogenase inhibitor.

Mogi Tatsushi T, Kawakami Takuro T, Arai Hiroyuki H, Igarashi Yasuo Y et al.

To identify antibiotics targeting to respiratory enzymes, we carried out matrix screening of a structurally varied natural compound library with Pseudomonas aeruginosa membrane-bound respiratory enzymes. We identified a succinate dehydrogenase inhibitor, siccanin (IC(50), 0.9 microM), which is a potent antibiotic against some pathogenic fungi like Trichophyton mentagrophytes and inhibits their mitochondrial succinate dehydrogenase. We found that siccanin was effective against enzymes from P. aeruginosa, P. putida, rat and mouse mitochondria but ineffective or less effective against Escherichia coli, Corynebacterium glutamicum, and porcine mitochondria enzyme. Action mode was mixed-type for quinone-dependent activity and noncompetitive for succinate-dependent activity, indicating the proximity of the inhibitor-binding site to the quinone-binding site. Species-selective inhibition by siccanin is unique among succinate dehydrogenase inhibitors, and thus siccanin is a potential lead compound for new chemotherapeutics.

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