Pyrindamycins A and B, new antitumor antibiotics.

Ohba, Kazunori; Watabe, Hiroomi; Sasaki, Tōru; Takeuchi, Yasuo; Kodama, Yoshio; Nakazawa, Tadashi; Yamamoto, H.; Shomura, Takashi; Sezaki, Masaji; Kondo, Shinichi

doi:10.7164/antibiotics.41.1515

Cited by 51 publications

(18 citation statements)

References 5 publications

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“…6,7 The present work thus demonstrates the first synthesis of racemic SF-2322 (3) by a short and efficient route. Extension of this work including applications of these findings in synthesizing optically active SF-2322 is in progress.…”

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confidence: 88%

“…4,5 Meanwhile, SF-2312 (3), a phosphonic acid antibiotic active against Gram-positive and Gram-negative bacteria, was isolated from Micromonospora sp. 6,7 Despite its unique structure in having a 1,5-dihydroxy-2-pyrrrolidone ring, attempts at preparation of 3 and the assignment of the stereochemistry have not been made so far. We describe herein the first, efficient synthesis of racemic SF-2312 (3) as a preliminary study for asymmetric synthesis of 3.…”

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confidence: 99%

“…Ethyl diethoxyphosphorylacetate served as the starting material for preparation of the 2-phosphorylpent-4-enohydroxamate derivative (6), the key precursor for the 1,5-dihydroxy-2-pyrrolidone ring formation (Scheme 1). The reported procedures 8 for preparation of ethyl 2-(diethoxyphosphoryl)pent-4-enoate (4a) from ethyl diethoxyphosphorylacetate was slightly modified and thus 4a was obtained in an improved yield (72%) together with the diallyl-substituted compound (4b) (11%).…”

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An Efficient Synthesis of Antibiotic SF-2312 (3-Dihydroxyphosphoryl-1,5-dihydroxy-2-pyrrolidone)

Hanaya¹,

Itoh

2010

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-N-Benzyloxy-2-diethoxyphosphoryl)pent-4-enamide (6) was prepared from ethyl diethoxyphosphorylacetate in a 3-step sequence. Oxidative cleavage of the terminal olefin of 6 with osmium tetroxide and sodium periodate afforded 1-benzyloxy-3-diethoxyphosphoryl-5-hydroxy-2-pyrrolidone (7). The first synthesis of racemic SF-2312 was achieved by treatment of 7 with trimethylsilyl bromide, followed by hydrogenolysis.Phosphonic acid antibiotics containing a hydroxamic acid function have attracted considerable interest in medicinal chemistry because of their antimicrobial activities. For example, fosmidomycin (1) 1 and its N-acetyl analog FR-900098 (2), 2 isolated from Streptomyces lavendulae and S. rubellomurinus sp., respectively, were found to be potent inhibitors for the 1-deoxy-D-xylulose 5-phosphate reductoisomerase. 3In recent years, a number of analogs of these compounds have been synthesized owing to the investigation of structure-activity relationships and development of antimalarial agents. 4,5 Meanwhile, SF-2312 (3), a phosphonic acid antibiotic active against Gram-positive and Gram-negative bacteria, was isolated from Micromonospora sp. 6,7 Despite its unique structure in having a 1,5-dihydroxy-2-pyrrrolidone ring, attempts at preparation of 3 and the assignment of the stereochemistry have not been made so far. We describe herein the first, efficient synthesis of racemic SF-2312 (3) as a preliminary study for asymmetric synthesis of 3.

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An Efficient Synthesis of Antibiotic SF-2312 (3-Dihydroxyphosphoryl-1,5-dihydroxy-2-pyrrolidone)

Hanaya¹,

Itoh

2010

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“…Ohba et al 5) have reported pyrindamycins A and B which are identical to duocarmycins C2 and Cl, respectively. The structures of duocarmycins were revealed by spectroscopic and chemical analysis6) (Fig.…”

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Duocarmycins, new antitumor antibiotics produced by Streptomyces; Producing organisms and improved production.

et al. 1991

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Six duocarmycins have been discovered during our search for newantitumor antibiotics and they showed extremely potent cytotoxic activity with IC50 values of l0"12 M~10~9Mon HeLaS3 cell. Three different producing strains isolated from soils were taxonomically assigned as Streptomyces. DuocarmycinA was unstable in culture broth, so improved culture conditions were designed to produce a high titer of duocarmycins Bl, B2, Cl and C2 which are halogenated seco-compounds of duocarmycin A. DuocarmycinSA, one of the most potent cytotoxic agents yet discovered, was shownto be more stable in culture media than duocarmycinA, despite the structural similarity on their spirocyclopropylhexadienone moiety. In contrast to the duocarmycinA fermentation, no halogenated seco-compounds of duocarmycin SA were detected in culture broth supplemented with Br~or Cl~. All duocarmycins could be produced using one producing strain with improved media and culture conditions. 1045 In the course of screening for new antitumor agents, we have isolated new potent antitumor antibiotics duocarmycins A (DC88-A)1}, Bl, B22), Cl (DC89-A1)3), C2 and SA (DC1 13)4) produced by Streptomyces. Ohba et al.5) have reported pyrindamycins A and B which are identical to duocarmycins C2 and Cl, respectively. The structures of duocarmycins were revealed by spectroscopic and chemical analysis6) (Fig. 1). Duocarmycins A and SAhave a spirocyclopropylhexadienone moiety which is known to be the DNA alkylating group of "left hand segment" of CC-10657~9). Recent studies have indicated that duocarmycin A can alkylate DNAin mechanisms similar to those of CC-106510'11*. The structural similarities suggest that duocarmycin SA also binds to DNAand alkylated DNAby a commonmechanism. Duocarmycins Bl, B2, Cl, C2 possess five or six-membered ring which were generated via attacking of bromide or chloride ion at the different carbon position on cyclopropane ring of duocarmycin A. Wehave succeeded in purification of duocarmycin A, however it seemed difficult to prepare duocarmycin A from culture broth in a large quantity because of its chemical instability: Duocarmycin A is unstable in aqueous solution and protic solvent, which will be published in a separate paper12). Therefore we studied improved conditions for large scale production and purification of the halogenated seco-compounds, duocarmycins Bl, B2, Cl , C2 which are more stable than duocarmycin A. On the other hand duocarmycin SAhas been shownto be more stable than duocarmycin A, so we investigated the improved production and purification of duocarmycin SA. Wereport here the taxonomic comparison of the three producing strains, increased production through manipulation of the culture conditions which could support production of all duocarmycins using any one of the producing strains.

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“…The molecular formula of duocarmycin The LD50 value of duocarmycin Bx (4) is 0.37 mg/kg (iv) in mice and that of duocarmycin B2 (5) is 0.28 mg/kg (iv). Duocarmycins B± (4) and B2 (5) are more potent than duocarmycins Qand C2. The antitumor activity of duocarmycins against mouse sarcoma 180 is summarized in Table 3.…”

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