Synthesis and antitumor activity of water-soluble enediyne compounds related to dynemicin a

Unno, Ryoichi; Michishita, Hisashi; Inagaki, Hideaki; Suzuki, Yoko; Baba, Yoshio; Jomori, Takahito; Nishikawa, Toshio; Isobe, Mitsuaki

doi:10.1016/s0968-0896(97)00037-0

Cited by 16 publications

(14 citation statements)

References 53 publications

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“…[62] In total, this route was completed in 26 steps in 0.3 %yield and employed an exo-selective Diels-Alder reaction as the key step.S everal analogues were also made by using the same approach. In the following years,c opious synthetic and SAR studies of enediyne analogues of the dynemicin core were performed by the groups of Schreiber, [61a,d] Wender, [63] Nicolaou, [61b, 64] Isobe, [65] Myers, [62a, 66] Danishefsky, [61g, 67] Maier, [68] Magnus, [69] and others. [64a,d,70] These studies probed the effects of triggering groups or initiators on the nitrogen atom or aryl ring, which could be activated under basic or photochemical conditions that could be mimicked by intracellular processes.T ethering devices were also investigated to aid target delivery,a sw ere deactivating groups that would modulate enediyne activity,aswell as detection devices that would facilitate mechanistic studies.…”

Section: From Dynemicin At Oadynemicin Analoguementioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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Section: From Dynemicin At Oadynemicin Analoguementioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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“…[35] Thus, an oxygen-containing functional group (R 2 ϭ OMe) on the benzene ring abolishes both the in vitro and the in vivo potencies. Varying the residues R 1 and R 2 the following trend emerged: Compound 48 (R 1 ϭ R 2 ϭ H) with no bulky groups at C-9 showed significant in vivo activity with a T/C of 170% at a daily dosage of 2.0 mg/kg for 4 days.…”

Section: ϫ7mentioning

confidence: 99%

“…[35] The antitumor activity of the analogs Scheme 12 could be further improved by attaching an aliphatic amino group at the C-9 position making them water-soluble. Among them compound 51 showed the most enhanced in A conceptually interesting extension of the use of a blocking group on the nitrogen atom was reported by vivo antitumor activity (T/C ϭ 222% at a daily dosage of 1.25 mg/kg for 4 days).…”

Section: ϫ7mentioning

confidence: 99%

Design and Synthesis of Dynemicin Analogs

Maier¹,

Boße

Niestroj

1999

Eur. J. Org. Chem.

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Dynemicin A is a member of the family of enediyne natural products. It is unique in that it combines a ten‐membered enediyne with an anthraquinone substructure. These features stimulated the development of synthetic approaches to the natural product itself and of analogs thereof. This review summarizes the total syntheses of dynemicin A. In addition, an overview of the known analogs is presented. The analogs can be classified according to the designed trigger mechanism. Most of the analogs contain a removable carbamate on the nitrogen atom. Others are quite similar to the natural lead in that they contain a quinone substructure, which upon reduction causes opening of the oxirane ring. In addition, there are analogs that contain an aromatic sector, the enediyne, and the oxirane ring but lack the nitrogen heterocycle. In these compounds the aryl ring assumes a different conformation from that in dynemicin A. Many of the simplified analogs proved to be quite active in vitro as well in vivo against murine tumor models. A highlight is compound 30 which is much more active than dynemicin A itself. However, looking at all analogs there is no clear‐cut correlation between the DNA‐cleaving ability at neutral pH and the in vitro results. From this one might conclude that there are possibly two mechanisms for antitumor activity. One involves diradical formation whereas the other might be due to a ligand‐receptor interaction.

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“…38 The procedure used for the synthesis of (Z)-enediyne 43 was also employed to prepare analogues of this compound that included enediynes 45, 39 46 40 and 47 40 (Figure 3), which were used as starting materials in the synthesis of a series of simple enediyne analogues of dynemycin A. 39,40 44a: R 1 = Ph; R 2 = H 44b: R 1 = Ph; R 2 = Me 44c: R 1 = Ph; R 2 = SiMe 3 44d: R 1 = 4-ClC 6 H 4 ; R 2 = H 44e: R 1 = Me; R 2 = SiMe 3 44f: R 1 = Me; R 2 = H In 1995 and in subsequent years, Banfi and Guanti synthesized a series of 10-membered cyclic enediynes of general formula 49, trans-fused with N-protected and Nunprotected β-lactams, which were named lactenediynes, via reaction schemes involving as a key step the reaction of (Z)-chloroenyne 2e with 3-(prop-2-ynyl)azetidin-2-ones 48 in a mixture of THF and piperidine at room temperature in the presence of catalytic amounts of PdCl 2 (PhCN) 2 , CuI and trimethylsilylacetylene (Scheme 14). [41][42][43][44][45] Scheme 14.…”

Section: Monolkynylation Reactions Of (E)-and (Z)-12dichloroethenementioning

confidence: 99%

Development and applications of highly selective palladium-catalyzed monocoupling reactions of (cyclo)alkenes and 1,3-alkadienes bearing two or three electrophilic sites and bis(enol triflates) with terminal alkynes

et al. 2013

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The motivation for writing this review with 558 references, which covers the literature up to the end of September 2012, is to fill a part of this gap by illustrating highly selective Pd/Cu-catalyzed and Cu-free Pd-catalyzed monoalkynylation reactions of (cyclo)alkenes and 1,3-butadienes bearing two or three identical or different electrophilic sites and bis(enol triflates) with terminal alkynes. However, Pd-catalyzed selective monocoupling reactions of 1-alkynes with (hetero)aryl halides or pseudohalides with two identical or different electrophilic sites will not be covered. Moreover, Pd-catalyzed monocoupling reactions of 1-alkynes with non-conjugated diene systems bearing an electrophilic site on each carbon–carbon double bond have also been considered to be beyond the scope of this review.\ud \ud In addition to describing and commenting on the aforementioned monoalkynylation reactions of (cyclo)alkenes and 1,3-dienes with two or three identical or different electrophilic sites and bis(enol triflates), emphasis has been placed on the use of Pd-catalyzed monoalkynylations of (cyclo)alkenes and 1,3-butadienes bearing two or three identical or different electrophilic sites and bis(enol triflates) as key steps of the syntheses of core structures and models of enediyne antitumor antibiotics, pharmacologically active compounds, and bioactive naturally occurring compounds including insect sex pheromone components, and fungal and plant metabolites. Moreover, the review has been focused on the formation of disubstituted acetylenic derivatives by one-pot site-selective Pd-catalyzed consecutive alkynylation reactions of di(pseudo)halogenated olefinic substrates with two different terminal alkynes. Where appropriate, the reasons for the observed stereo-, site-, and/or chemoselectivities of the reported Sonogashira-type monoalkynylation reactions have been mentioned and discussed

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Synthesis and antitumor activity of water-soluble enediyne compounds related to dynemicin a

Cited by 16 publications

References 53 publications

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Design and Synthesis of Dynemicin Analogs

Development and applications of highly selective palladium-catalyzed monocoupling reactions of (cyclo)alkenes and 1,3-alkadienes bearing two or three electrophilic sites and bis(enol triflates) with terminal alkynes

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