Activation dynemicin

Shair, M.D. Yoon, T. Chou, T.-C. Danishefsky, S. J. Enediyne quinone imines truncated biologically active dynemicin congeners. Angew. Chem., Int. Ed. Engl. 1994, 33, 2477-2479 Shair, M.D. Yoon, T.Y. Mosny, K.K. Chou, T.C. Danishefsky, S.J. The total synthesis of dynemicin A leading to development of a fully contained bioreductively activated enediyne prodrug. J. Am. Chem. Soc. 1996. 118, 9509-9525. 

Several novel natural products with an intriguing system containing the cis-endiyne moiety have attracted considerable attention from chemists in recent years. Several derivatives with this characteristic skeleton have now been isolated neocarzinostatin,96 esperamicin,97 calicheamicin y. 9S and dynemicin Ai." The high antitumor activity of these compounds is based on an elegant... 

Figure 2 Examples of polyketides. Polyketides demonstrate a broad range of biological activities, including antibiotic (oxytetracycline and erythromycin), antitumor (doxorubicin and dynemicin), antiparasitic (avermectin), and immunosuppressive (FK506). Monensin is used as a bovine feed supplement and an anticoccidial agent.

These novel, extremely potent antibiotics all possessed one very unusual chemical structural feature an enediyne fragment within a ring. The first discovered was neocarzinostatin (NSC), which was found to be composed of a protein (NSC apoprotein) and the neocarzinostatin chromophore 30 in a 1 1 complex. The biological activity is associated with the NSC chromophore. However, it took until the discovery of the calichaemicin " 31 and esperamicin 32 families in 1987 to really gamer the broad attention of chemists. Other enediyne antibiotics include the dynemicin family, the kedarcidin chromophore, namenamicin, the C-1027 chromophore,and uncialamycin. " ... 

Kraka, E. Tuttle, T Cremer, D. Design of a new warhead for the natural enediyne dynemicin a. An increase of biological activity, J. Phys. Chem. B 2008, 112, 2661-2670. 

Other enediyne antitumor antibitotics (neocarzinostatin, esperamycin, dynemicin) may have similar or different mechanisms of activation, but they all use cy-cloaromatization as the key step in generating the DNA-damaging species. 

Two derivatives, compound 94, which bears an esperamicin core with an epoxide trigger, and 95, which is a hybrid between esperamicin and dynemicin A cores,have been reported (Scheme 19.25). Both compounds, after trifluoroacetamide removal, underwent cycloaromatization and showed an interesting antitumor activity in vivo in mice. 

Guanti, G. Riva, R. Simplified dynemicin analogues diastereoselective synthesis and evaluation of their activity against plasmid DNA. Org. Biomol. Chem. 2003, 1, 3967 3976. 

The special fascination of strained cyclic enediynes lies in their intrinsic tendency to undergo thermal cyclisation. This aspect has been stimulating the research activities on enediynes since their beginnings more than 20 years ago, [1] and it is this reactivity of the enediyne structure that brings about the pharmacological effectiveness of natural products, like Dynemicin A. [2]... 

The second activation cascade indicated in Scheme 7-70 for the Nicolaou dynemicin model systems was demonstrated through the triggering of the phenol derivative 352, cleanly produced by photolytic deprotection of the o-nitrobenzyl ether 351 (Scheme 7-74) (119, 120]. Tlreatment of 352 with nucleoplules (e.g., EtOH, EtSH, -PrNH2) provided the aromatization... 

Scheme 7-76 Synthesis and activation of dynemicin A model 366 (Wender et al.).

Kedarcidin. A further enediyne antibiotic with antitumor activity besides the calicheamicins, espera-mycins, dynemicins, and neocarzinostatins. 

Cultures of the bacterium Micromonospora chersina produce dynemicin A, a novel substance containing a double bond and two triple bonds in a ten-membered ring (an enediyne). Dynemicin A has attracted interest because of its unusual structure as well as its interesting biological activity. It has the ability to cleave DNA by a novel mechanism, which may lead to the development of anticancer drugs that are based on the enediyne structure. 

Scheme 1. Proposed mechanism for the biological activity of dynemicin A.

In this section, only enediyne antibiotics bearing an epoxy moiety will be treated. The enediynes are a class of natural products that consist of a unique molecular architecture and exhibit phenomenal antitumor activity. They are stmcturally characterized by an enediyne core containing two acetylenic groups conjugated to a double bond or incipient double bond within a nine-membered ring, such as neocarzinos-tatin 301, or a 10-membered ring, such as dynemicin A 304a. The enediyne cores... 

Among these reactions, three were recognized with a Nobel Prize in Chemistry in 2010. The Nobel Prize was awarded on the basis of practical use in the industrial sector. Heck reactions were used for the synthesis of more than 100 kinds of natural products and physiologically active substances, Negishi reactions were used for the synthesis of pumiUotoxins A (PTXs) and hennoxazole A, and Suzuki-Miyaura reactions were used for the syuthesis of dynemicin A and dragmacidin F [ 100,101]. 

The final example in the table (example 5, Table 6.9) is one of a class of similar cyclizations found in several families of antibiotics. For example, it has been argued that the activity of antibiotics such as Dynemicin A (Figure 6.17) results from initial binding (intercalation) of the antibiotic into the minor groove of deoxyribonucleic acid (DNA Chapter 14) followed by cycloaromatization of the enediyne system to produce a diradical intermediate. The diradical then irreversibly finks to the DNA by hydrogen abstraction, damaging it permanently. 

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