Studies concerning the antibiotic actinonin. Part IV. Synthesis of structural analogues of actinonin by the mixed anhydride method

Broughton, Barbara J.; Warren, Peter J.; Wooldridge, K. R. H.; Wright, Derek E.; OLLIS, W. DAVID; Wood, Ronald J.

doi:10.1039/p19750000842

Cited by 6 publications

(4 citation statements)

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“…93 About 20 years later, actinonin was also obtained from another strain referenced MG848-hF6 and its inhibition against APN was found to be competitive with the substrate. 94 The structural study and the chemical synthesis of 13 and some analogues have aroused numerous works [95][96][97][98][99][100][101][102] completed by a structure-activity relationship investigation dealing with anti bacterial properties observed in this actinonin series. 103…”

Section: A Naturally Occurring Apn/cd13 Inhibitorsmentioning

confidence: 99%

Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospects

Bauvois¹,

Dauzonne²

2005

Med. Res. Rev.

233

162

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Aminopeptidase N (APN)/CD13 (EC 3.4.11.2) is a transmembrane protease present in a wide variety of human tissues and cell types (endothelial, epithelial, fibroblast, leukocyte). APN/CD13 expression is dysregulated in inflammatory diseases and in cancers (solid and hematologic tumors). APN/CD13 serves as a receptor for coronaviruses. Natural and synthetic inhibitors of APN activity have been characterized. These inhibitors have revealed that APN is able to modulate bioactive peptide responses (pain management, vasopressin release) and to influence immune functions and major biological events (cell proliferation, secretion, invasion, angiogenesis). Therefore, inhibition of APN/CD13 may lead to the development of anti-cancer and anti-inflammatory drugs. This review provides an update on the biological and pharmacological profiles of known natural and synthetic APN inhibitors. Current status on their potential use as therapeutic agents is discussed with regard to toxicity and specificity.

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Section: A Naturally Occurring Apn/cd13 Inhibitorsmentioning

confidence: 99%

Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospects

Bauvois¹,

Dauzonne²

2005

Med. Res. Rev.

233

162

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“…3-Alkyl-dihydro-furan-2,5-diones (3-alkyl succinic anhydrides) and (E)-3-alkylidene-dihydro-furan-2,5-diones [(E)-3-alkylidene succinic anhydrides] are both important class of compounds due to their utility as intermediates in the synthesis of important targets such as natural antibiotics, 1,2 pyrrolidines, 3 metalloproteinase inhibitors, 4 inhibitors towards human leukocytes, 5 cephalotaxine, 6 and monoesters of alkylated succinic acids. 7 Although several methods have been reported [3][4][5][6][7][8][9][10][11][12] for the preparation of the title compounds, they seem not of general applicability.…”

mentioning

confidence: 99%

Nitroalkanes and Dimethyl Maleate as Source of 3-Alkyl Succinic Anhydrides and (E)-3-Alkylidene Succinic Anhydrides

Ballini¹,

Bosica²,

Fiorini³

et al. 2002

Synthesis

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Nitroalkanes react with dimethyl maleate giving a tandem Michael addition/elimination of nitrous acid. The obtained (E)-2-alkylidene dimethyl succinates are: (i) reduced to the corresponding 2-alkyl dimethyl succinates which after hydrolysis produce 1,4-dicarboxylic acids that are prone to convert into the corresponding 3-alkyl succinic anhydrides or (ii) hydrolysed to (E)-2-alkylidenesuccinic acids that are easily cyclised to (E)-3-alkylidene succinic anhydrides.3-Alkyl-dihydro-furan-2,5-diones (3-alkyl succinic anhydrides) and (E)-3-alkylidene-dihydro-furan-2,5-diones [(E)-3-alkylidene succinic anhydrides] are both important class of compounds due to their utility as intermediates in the synthesis of important targets such as natural antibiotics, 1,2 pyrrolidines, 3 metalloproteinase inhibitors, 4 inhibitors towards human leukocytes, 5 cephalotaxine, 6 and monoesters of alkylated succinic acids. 7 Although several methods have been reported 3-7,8-12 for the preparation of the title compounds, they seem not of general applicability.Recently, an interesting methodology for the preparation of 3-alkyl succinic anhydrides has been published. 7d However, a more efficient procedure for the synthesis of both the anhydrides is still desirable.Over the last decade aliphatic nitro compounds have demonstrated to be a valuable source for the preparation of alkylated heterocyclic derivatives. 13 In continuation of our studies we wish to report here a general synthesis of both 3-alkyl succinic anhydrides 6 and (E)-3-alkylidene succinic anhydrides 8, using nitroalkanes 1 and dimethyl maleate 2 as common starting materials. Conjugate addition (Scheme) of the nitronate, derived from the nitro compound 1, to 2 in acetonitrile with DBU as base allows the formation of the product 3, essentially as single stereoisomer of E configuration. 13a,14 The adduct 3 is obtained pure enough and can be directly used without purification as the key building block for the synthesis of the anhydrides 6 or 8 by two different synthetic sequences.Scheme Synthesis of compounds 6a-k and 8a-e.Thus, chemoselective hydrogenation (10% Pd/C as catalyst) of the C=C double bond of the crude compound 3 yields the saturated diester 4 (80-98% from 1). Saturated diester 4 after hydrolysis with aqueous 2% sodium hydroxide and ethanol at reflux temperature provides the dicarboxylic acid 5 (63-90%).Although several methods are available for the conversion of 1,4-dicarboxylic acids into the corresponding anhydrides, we chose acetyl chloride 15 as a dehydrating agent for the preparation of 6 in high yields (85-98%, Table 1). On the other hand, the basic hydrolysis of the crude adduct 3 (2% sodium hydroxide solution) allows the formation of the 2-alkylidene succinic acid 7 (71-95%). The 2-alkylidene succinic acids 7 are converted to the (E)-2-alkylidene succinic anhydrides 8 in excellent yield (87-98%) following the previous procedure for the anhydrides 6. R R 1 NO 2 COOMe COOMe COOMe COOMe R R 1 COOH COOH R R 1 O R 1 R O O COOMe COOMe R R 1 COOH COOH R R 1 O R 1 R O...

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“…Albeit its antibacterial activity was later explained by inhibition of the RNA biosynthesis, the exact target could not be identified at the time [90]. The first total synthesis by Anderson et al [91] enabled the synthesis of a multitude of class analogs [92][93][94][95] finally providing a structure-activity relationship [96]. This exemplifies the enabling contribution of total syntheses to the process of gaining deeper understanding of the biological properties.…”

Section: Natural Productsmentioning

confidence: 99%

Role of Natural Products in Drug Discovery

Lachance

Wetzel

Waldmann

2010

Lead Generation Approaches in Drug Discovery

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Studies concerning the antibiotic actinonin. Part IV. Synthesis of structural analogues of actinonin by the mixed anhydride method

Cited by 6 publications

References 0 publications

Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospects

Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospects

Nitroalkanes and Dimethyl Maleate as Source of 3-Alkyl Succinic Anhydrides and (E)-3-Alkylidene Succinic Anhydrides

Role of Natural Products in Drug Discovery

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