Activation enediyne

Scheme 10 Metal coordination activates enediynes by drastically reducing the distance between the acetylenic carbons.

The synthesis of new selectively activated enediyne prodrugs (I, Fig. 11) has been reported to start from suitably substituted (3-lactams [269]. 

An alternative to thermal cycloaromatization is represented by photo-activable enediyne systems, where a stable enediyne molecule is activated... 

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. 

Neocarzinostatin is a complex protein carrying the anti-tumor active enediyne ring chromophore. Because of the labile chromophore reflecting its... 

With the mechanistically interesting new approaches described here the spectrum of methods for the synthesis of strained cyclic enediynes could be enlarged markedly. It is to be expected that the search for simple pharmacologically active enediyne derivatives will benefit accordingly. 

Figure 2. Depiction of 02-dependent DNA strand cleavage induced by activated enediynes. (a) Mechanism of nucleophilic activation and subsequent radical chemistry leading to DNA strand breaks for NCS. (b) Mechanism of strain relaxation-triggered activation and subsequent radical chemistry leading to DNA strand breaks for C-1027.

Like metal ions, which change activation barriers and affect the kinetics of Bergman cyclizations, the organometallic reagents also activate enediynes. It was noted above that the Myers-Saito cyclization occurs at a much lower temperature than the Bergman cyclization of enediynes... 

Alabugin, I.V. and Manoharan, M. (2003) Reactant destabilization in the Bergman cyclization and rational design of light- and pH-activated enediynes. Journal Physical Chemistry A, 107(18), 3363-3371. 

D receptors and their associated coactivators heat shock proteins. Additional possibilities include the glucocortocoid and mineralcorticoid receptors and a number of orphan receptors, e.g., the aryl hydrocarbon receptor. In the latter case, it has aheady been demonstrated that degradation can be effected by a thermally activated enediyne thus, a photochemical variant could be forthcoming. 

An alternative approach to the antitumor active enediyne systems (cf. eq 47) using Nicholas cations has been extensively studied and applied to the dynemycin core structure (eq 53). Another example of the use of such cations in forming strained rings is the preparation of a cobalt complex of a trithia-crown ether (eq 54), which has been shown to complex Cu and Ag ... 

The cycloaromatization of enediynes, having a structure like 1, proceeds via formation of a benzenoid 1,4-diradical 2, and is commonly called the Bergman cyclization. It is a relatively recent reaction that has gained importance especially during the last decade. The unusual structural element of enediynes as 1 has been found in natural products (such as calicheamicine and esperamicine) which show a remarkable biological activity... 

The tightly bound chromophore could be extracted from the protein with methanol [186], and the major component of the extract was determined to have the enediyne structure 116 (Figure 11.21), related to chromophores of other chromoprotein antitumor agents such as neocarzinostatin. Additional minor components were extracted, variously containing an OH group instead of OMe attached to the enediyne core, with Cl instead of OMe when chloride was present in the buffer salt, or with OEt instead of OMe when ethanol was used for the extraction. Another byproduct was isolated in the form of structure 117, consistent with a facile cy-doaromatization reaction as observed for all other enediyne antibiotics. Surprisingly, 117 also displayed antibiotic and antitumor activity, perhaps due to alkylation of DNA or protein by the aziridine. The interpretation of these results was that 116 and the other enediyne byproducts were merely artifacts of the extraction procedure and that the true structure of the maduropeptin chromophore is the aziridine 118. 

The anticancer activity of complex natural products having a cyclodecenediyne system [for a review see <96MI93>] has prompted the synthesis of 54 (X = CH2 and OCH2) <96CC749> and 55 (R = a-OH and p-OH) <95AG(E)2393> on the basis that such compounds are expected to develop anticancer activity as the P-lactam ring opens. This is because cycloaromatization can only occur in the monocyclic enediyne and the diradical intermediate in the cyclization is thought to be the cytotoxic species. 

A similar pre-orientation involving unsaturated carbon chains was operative on generating twelve-membered enediyne 23 and arenediyne lactams 24 [7]. The seco methylesters 21 and 22 were cleaved with LiOH, the corresponding carboxylic acids underwent cyclizations after activation with 2-fluoro-pyridinium tosylate 25 [8]. Dimerization products were found as by-products (<10%). It should be pointed out, that the lactamization succeeded in a single step in about 75% yield by treating the seco-methylesters 21 and 22 with Me3Al in refluxing methylene chloride. Obviously, the latter route was more convenient (Scheme 5). 

While enediyne natural products are efficient DNA cleaving agents, synthetic enediynes have been utilized widely to study the mechanistic details and obtain more efficient DNA cleavage activity. Simple enediynes (Fig. 8), with no binding units, show DNA cleavage albeit at very high concentra-... 

An extensive computational analysis expanded the range of the c-d distances for reactive cyclic enediynes to 2.9-3.4 A.38 By comparing unsubstituted enediynes with dialkyl-substituted enediynes, it was found that the activation enthalpy is dependent on factors other than the c-d distance and that reactivity hinges on a subtle interplay of steric and electronic effects that accompany distortion caused by incorporation into a macrocycle. For example, since alkyl substituents stabilize acetylenic bonds to a greater extend than olefinic bonds,39 such substituents stabilize the starting material, thus increasing both the activation barrier and the reaction endothermicity. 

The antiaromatic region is not important for the reactivity of the parent enediyne because the activation energy is determined only by the energy difference between the reactant and the TS. However, for the cyclic enediynes in Fig. 7 in which the C1-C6 distances are 3.39 and 2.92 A, respectively, antiaromaticity of the reactant should be relevant to the reaction kinetics. In addition, the role of repulsion between the in-plane filled orbitals is accentuated by a parallel decrease in the attractive two-electron interaction between the re and re orbitals which vanishes at the 3.2 A distance between the terminal carbon atoms. 

Strain-based systems work the same way as the cyclic enediynes they reduce the c-d distance in the molecule. The first example was provided by Buchwald and coworkers,45 who used metal complexation of a PPh2 substituted enediyne to produce a species with considerably lower activation barrier (compared to the non-coordinated enediyne) (Scheme 10). 

Scheme 11 Model systems illustrating enediyne activation through metal complexation.

Scheme 12 Tetradentate enediyne ligands used to achieve enediyne activation by metal complexation while avoiding dimerization at the metal.

Fig. 12 Correlation between the calculated activation energy of the Bergman cyclization and the product of natural charges at the terminal acetylenic atoms of benzannelated enediynes. Only para substituents obey the correlation. Adapted from reference49.

Since four-electron repulsion is the dominant factor in the reactant destabilization, any structural perturbation that either increases electron repulsion in the reactant or decreases the electron repulsion in the TS will decrease the activation energy for the cyclization. One way for placing an accelerating substituent in direct spatial proximity to the in-plane re-orbitals is to use appropriate ortho substituents in benzannelated enediynes. 

Fig. 15 Predicted cooperative effects on activation energies (in kcal/mol) at the B3LYP/ 6-31G level for model enediynes ( push and pull denote through-space repulsive (steric) and attractive (H-bonding) interactions of ort/zo-substituents with in-plane 71-orbitals of an adjacent acetylene moeity).

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