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

doi:10.1248/cpb.44.1723

Cited by 40 publications

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“…Duocarmycins A and SA ( 1b ) have a unique cyclopropane ring responsible for the sequence-selective alkylation of double-stranded DNA mediating N3 adenine covalent adduct formation . This mechanism is similar to that of CC-1065 ( 2 ) which has been reported to show a high cytotoxicity. , KW-2189 ( 3b ), selected as the best compound in analogues of A-ring pyrrole derivatives of duocarmycin B2, showed good stability in the culture medium and aqueous solubility greater than 10 mg/mL. , It also showed strong activities against murine ascitic and human solid tumors 7b.…”

Section: Introductionsupporting

confidence: 54%

“…The segment-A (Seg-A) containing a spirocyclopropylhexadienone moiety is necessary for the formation of covalent binding with DNA. Our previous results indicate that the Seg-A structure will influence the electrophilicity of cyclopropane 7c. On the other hand, the segment-B (Seg-B) of duocarmycin has been considered to play an important role for noncovalent binding to the minor groove of DNA .…”

Section: Introductionmentioning

confidence: 99%

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New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups

et al. 1999

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A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups

et al. 1999

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“…Reduction of 8 a ± c, followed by coupling with compound 5 by using FDPP, produced 9 a ± c. After subsequent deprotection with 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU), the carboxylic acids 10 a ± c were activated with 1,1'-carbonylimidazole (CDI), as previously described [10] to give 11 a ± c. The alkylating moiety, segment A of DU-86 (CPI), was prepared through five steps according to the reported procedures. [12] Finally, the synthesis of conjugates 12 ± 14 was accomplished by coupling 11 a ± c and CPI, with a moderate yield. After purification by HPLC, the hairpin polyamide ± CPI conjugates 12 ± 14 were used for DNA alkylation experiments.…”

Section: Resultsmentioning

confidence: 99%

Molecular Design of a Pyrrole–Imidazole Hairpin Polyamides for Effective DNA Alkylation

et al. 2002

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“…KW-2189 (69), a semi-synthetic derivative of duocarmycin B2 (4) [107], was selected for clinical trials due to favorable water solubility (10 mg/mL) and antiproliferative activity in experimental animal models [108][109][110]. In spite of the deactivating carbamate functionality, KW-2189 (69) has been shown to form a covalent adduct with adenine at N3, although it is a 1000-fold more active after cleavage of the carbamoyl moiety by carboxyl esterases in vivo [110,111].…”

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confidence: 99%

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

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CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products

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Synthesis and Antitumor Activity of Duocarmycin Derivatives: Modification of Segment A of Duocarmycin B2.

Cited by 40 publications

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New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups

New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups

Molecular Design of a Pyrrole–Imidazole Hairpin Polyamides for Effective DNA Alkylation

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

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