Synthesis and Background Chemistry of 15‐Deoxyspergualin

Maeda, Kenji; Umeda, Yohtaro; Saino, Tetsushi

doi:10.1111/j.1749-6632.1993.tb35859.x

Cited by 38 publications

(28 citation statements)

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“…15-Deoxyspergualin (DSG; 1-amino-19-guanidino-11-hydroxy-4, 9, 12-triazanona-decane-10, 1-3-dione) is a synthetic analogue of spergualin, a natural product of the bacterium Bacillus laterosporus (Maeda et al, 1993;Figure 5). A long list of more stable analogues have been designed, synthesized and evaluated over years.…”

Section: Figurementioning

confidence: 99%

“…In particular they suggest that lysosomes can be mechanistically involved in autophagy activation in addition to their well-known implication in autophagic degradation. This work proposes another interactive link between CMA and macroautophagy.15-Deoxyspergualin (DSG; 1-amino-19-guanidino-11-hydroxy-4, 9, 12-triazanona-decane-10, 1-3-dione) is a synthetic analogue of spergualin, a natural product of the bacterium Bacillus laterosporus (Maeda et al, 1993; Figure 5). A long list of more stable analogues have been designed, synthesized and evaluated over years.…”

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Pharmacological regulators of autophagy and their link with modulators of lupus disease

Gros

Muller

2014

British J Pharmacology

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Autophagy is a central regulator of cell survival. It displays both anti-and pro-death roles that are decisive in the maintenance of cell homeostasis. Initially described in several eukaryotic cellular models as being induced under nutrient stress favouring survival by energy supply, autophagy was found later to display other decisive physiological roles, especially in the immune system. Thus, it is involved in antigen presentation and lymphocyte differentiation as well as in the balance regulating survival/death and activation of lymphocytes. Autophagy therefore appears to be central in the regulation of inflammation. The observation that autophagy is deregulated in systemic lupus erythematosus is recent. This discovery revives the programme dealing with the design and development of pharmacological autophagy regulators in the therapeutic context of lupus, a debilitating autoimmune disease that affects several million people in the world. A large number of molecules that positively and negatively regulate autophagy have been described, most of them with therapeutic indications in cancer and infection. Only a few, however, are effectively potent activators or inhibitors endowed with experimentally demonstrated selective properties. In this review article, we highlight the most relevant ones and summarize what we know regarding their mechanism of action. We emphasize the link between pharmacological regulators of autophagy and inducers or inhibitors of lupus disease and discuss the fundamental and pharmacological/therapeutic interest of this functional interplay. AbbreviationsCMA, chaperone-mediated autophagy; CQ/HCQ, chloroquine/hydroxychloroquine; HSPA8/HSC70, heat shock cognate protein of 70 kDa; LAP, LC3-associated phagocytosis; LC3, microtubule-associated protein light chain 3; MHC-I/II, MHC class I or MHC class II; mTOR, mammalian target of rapamycin; PRR, pattern recognition receptors; SLE, systemic lupus erythematosus TLR 9 RapamycinThis Table lists the protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013a). Autophagy and its implication in human diseasesAutophagy is a catabolic process related to lysosomal degradation. Opposed to heterophagy, which implies degradation of substrates from outside the cell, autophagy catabolizes the cytoplasmic content. There are three main pathways involved in autophagy. The first one, called microautophagy, involves the direct engulfment of cytosolic material into the lysosome. Its core molecular machinery and regulation as well as its possible implication in human diseases are still poorly understood. In this review, we will focus the first part of our comments on the two other types of autophagy, namely, macroautophagy and chaperone-mediated autophagy (CMA). Historically, the term 'autophagy' was proposed by Christian De Duve in the ...

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Pharmacological regulators of autophagy and their link with modulators of lupus disease

Gros

Muller

2014

British J Pharmacology

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“…15-Deoxyspergualin (DSG; 1-amino-19-guanidino-11-hydroxy-4, 9, 12-triazanona-decane-10, 1-3-dione; generic name, Gusperimus) is a synthetic analogue of spergualin, a natural product of the bacterium Bacillus laterosporus (4). Spergualin, a peptidomimetic compound containing a spermidine-moiety within its structure, was discovered in 1981 by Umezawa et al in a culture filtrate while screening for natural products that inhibit the transformation of chicken embryo fibroblasts through Rous sarcoma virus (5).…”

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15-Deoxyspergualin in Patients with Refractory ANCA-Associated Systemic Vasculitis

Birck

Warnatz²,

Lorenz

et al. 2003

Journal of the American Society of Nephrology

139

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ABSTRACT. The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/μl followed by a rest until at least a WBC of 4000/μl was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count. E-mail: rainer.birck@med5.ma.uni-heidelberg.de

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“…IT was filter-sterilized (0.22 pm) prior to use. DSG (a gift from Novartis, Basel, Switzerland) was a racemic mixture prepared according to a method based on the procedure described by Maeda et al [13]. As per the protocol, DSG was administered to all recipients at 2.5 mg/kg i.v.…”

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Particle-induced circulatory disturbances in transplanted rhesus macaque kidneys

et al. 2003

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We have demonstrated the presence of crystalline particles in University of Wisconsin (UW) solution used to perfuse rhesus monkey kidney transplants. These particles were visible in obstructed blood vessels and associated with immediate graft thrombosis and necrosis. This occurred in 25.7% of kidneys perfused with UW solution and transplanted into young, unsensitized recipients. Two molecular species of crystals were defined by mass spectrometry. The particle size ranged from 3 to greater than 100 pm, with a preponderance of particles less than 25 pm in diameter. Such particles are not removed by 40-pm filtration, but can be removed by centrifugation. With extensive use of U W solution for organ storage, the potential for particle-induced damage in small vessels in both experimental and human transplants needs to be carefully scrutinized.

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Synthesis and Background Chemistry of 15‐Deoxyspergualin

Cited by 38 publications

References 9 publications

Pharmacological regulators of autophagy and their link with modulators of lupus disease

Pharmacological regulators of autophagy and their link with modulators of lupus disease

15-Deoxyspergualin in Patients with Refractory ANCA-Associated Systemic Vasculitis

Particle-induced circulatory disturbances in transplanted rhesus macaque kidneys

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