154889-68-6Relevant articles and documents
Practical synthesis of the high-quality antitumor agent KW-2189 from duocarmycin B2 using a facile one-pot synthesis of an intermediate
Kinugawa, Masahiko,Nagamura, Satoru,Sakaguchi, Akihiko,Masuda, Yoshiaki,Saito, Hiromitsu,Ogasa, Takehiro,Kasai, Masaji
, p. 344 - 350 (2013/09/08)
A facile and large-scale preparation process of a potent antitumor agent KW-2189 (2), derived from the antitumor antibiotic duocarmycin B2 (1), has been developed. This new synthetic route required three steps: (i) one-pot carbamoylation and subsequent reduction, (ii) Wagner-Meerwein rearrangement of the methoxycarbonyl group for the production of the pyrrole compound 6, and (iii) formation of the hydrobromide salt 2. The key strategic improvement was to obtain good quality hydroxy compound 4 in a reasonable yield without isolation of the unstable keto intermediate 3a. During commercial-scale production at a scale of about 50 g, this strategy provided high-quality KW-2189 (2) in a 55% overall yield from 1. Potential degradation compounds 7-9 were also synthesized and shown to be absent in the KW-2189 (2) prepared.
Novel syntheses of optically active CC-1065, U-73,975(adozelesin), U-80,244(carzelesin), U-77,779(bizelesin), KW-2189, and DU-86
Fukuda, Yasumichi,Furuta, Hirosuke,Shiga, Futoshi,Asahina, Yoshikazu,Terashima, Shiro
, p. 2303 - 2308 (2007/10/03)
The title syntheses were achieved by the method featuring oxidative cyclization of the enamino esters [(S)-13 and (S)-24] derived from the 5-aminoindoline [(5)-12], acylation with various structural types of indole-2-carboxylic acids, and formation of cyclopropapyrroloindole moieties.
The synthesis of [3H]KW-2189, a novel active antitumor antibiotic
Nagamura, Satoru,Kinugawa, Masahiko,Ogasa, Takehiro,Saito, Hiromitsu
, p. 471 - 477 (2007/10/03)
The synthesis of [3H]KW-2189, 2, a novel active antitumor antibiotic, is described. The key intermediate 6 in the synthesis, was synthesized in four steps from duocarmycin B2 (1). Treatment of 6 with [3H]methyl iodide in the presence
Wagner-Meerwein rearrangement of duocarmycins
Nagamura, Satoru,Kanda, Yutaka,Asai, Akira,Kobayashi, Eiji,Gomi, Katsushige,Saito, Hiromitsu
, p. 933 - 939 (2007/10/03)
We found that treatment of the 8-O-protected-3-hydroxy derivatives of duocarmycin B2 (DUMB2, 1c) with camphorsulfonic acid (CSA) in toluene interestingly gave A-ring pyrrole analogs of DUMB2 (1c) in good yields. Their structures were unambiguously elucidated on the basis of NMR and mass spectrometry, and the mechanism was considered to be a Wagner-Meerwein type rearrangement. On the other hand, treatment of the 9-O-protected-3-hydroxy derivatives of duocarmycin B1 (1b) with CSA afforded different rearrangement products. In the case of bulky groups at the 9-O position, such as a tert- butyldimethylsilyl group, normal A-ring pyrrole analogs were obtained. Under the same condition, however, the 9-O-N,N-dimethylcarbamoyl-3-hydroxy compound of lb Rase a spiro compound, which was derived from a 1, 2-shift of the methoxycarbonyl group and a bonding between the C-8 position and the C-2' position. Compounds having a protective group of medium size gave a mixture of the normal rearrangement and the spiro derivative.
Synthesis and antitumor activity of duocarmycin derivatives: Modification of segment A of duocarmycin B2
Nagamura, Satoru,Asai, Akira,Kanda, Yutaka,Kobayashi, Eiji,Gomi, Katsushige,Saito, Hiromitsu
, p. 1723 - 1730 (2007/10/03)
Several A-ring pyrrole derivatives of duocarmycin B2 were synthesized effectively from the 3-hydroxy compounds by utilizing an interesting acid- catalyzed rearrangement, their anticellular activity was preliminarily evaluated by assays of growth inhibition of HeLa S3 cells (in vitro) and antitumor activity against murine sarcoma 180 (in vivo). The 8-O-N,N- dialkylcarbamoyl derivatives of the A-ring pyrrole compound showed remarkably potent in vivo antitumor activity, superior to that of duocarmycin B2. These derivatives were subjected to further biological evaluation. They exhibited potent antitumor activity toward murine solid tumors including M5076 sarcoma, B-16 melanoma and Colon 26 adenocarcinoma. Their most noteworthy feature was their efficacy against various human xenografts including LC-6 (lung), St-4 (stomach), and Co-3 (colon).
