Neocarzinostatin chromophor

The Parent Carbocyclic Subunit of Neocarzinostatin Chromophore A WenderTC, 1988,29,909. 

Enediynes with ethylene carbonate fragment in the synthesis of dienediyne models of the biradical-forming and DNA-cleaving natural neocarzinostatin chromophore 99SL657. 

Scheme 18.57 Postulated mechanism of the DNA cleavage by the neocarzinostatin chromophore 168 [162].

Since the double bond between C5 and C6 of the enynecumulene 169 is not required for the Myers-Saito cyclization, a large number of enyneallenes have been synthesized as model compounds for the neocarzinostatin chromophore and tested for DNA-cleaving activity in recent years, with the results having already been summarized extensively (cf. Chapter 20) [162]. 

Similarly, ab initio calculations on the thermal reaction of propene forming methyl-cyclopentane suggested a three-step biradical reaction with 1,4-biradical and 1,5-biradical as intermediates. Quantum-chemical calculations have been carried out for the cyclization of the neocarzinostatin chromophore cyclonona-l,2,3,5-tetraen-7-yne to 1,5-didehydroindene biradical. The degree of stereoselectivity of the Diels-Alder reaction of 2-methylfuran and maleic acid in water has been found to reduce significantly in the presence of heavy atoms. Taking into account the relatively low concentration (3.5-7 m) of heavy-atoms, and the rapid fall off of the heavy-atom effect with distance, these results show that a large portion of the Diels-Alder reaction occurs via diradical intermediates. " ... 

Povirk LF, Goldberg IH (1985a) Detection of neocarzinostatin chromophore-deoxyribose adducts as exonuclease-resistant sites in defined-sequence DNA. Biochemistry 24 4035-4040 Povirk LF, Goldberg IH (1985b) Endonuclease-resistant apyrimidinic sites formed by neocarzinostatin at cytosine residues in DNA evidence for a possible role in mutagenesis. Proc Natl Acad Sci USA 82 3182-3186... 

Povirk LF, Goldberg IH (1986) Base substitution mutations induced in the cl gene of lambda phage by neocarzinostatin chromophore correlation with depyrimidination hotspots at the sequence AGC. Nucleic Acids Res 14 1417-1426... 

Povirk LF, Dattagupta N, Warf BC, Goldberg IH (1981) Neocarzinostatin chromophore binds to deoxyribonucleic acid by intercalation. Biochemistry 20 4007-4014 Powers EL, Gampel-Jobbagy Z (1972) Water-derived radicals and radiation sensitivity of bacteriophage T7. Int J Radiat Biol 21 353-359... 

Figure 3.4 Mechanism of action of the neocarzinostatin chromophore. Thiol addition initiates conversion to an allenic intermediate, which undergoes cyclisation to form a diradical intermediate. Formation of this diradical in a DNA-bound state leads to radical abstraction and subsequent strand cleavage. The star notes the location of the reactive enediyne functionality of the neocarzinostatin chromophore.

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. " ... 

Unlike the other naturally occurring enediyne molecnles, neocarzinostatin chromophore (30) is activated into an enyne-butatriene. This unusual cumulene 57 undergoes a cyclization analogous to the Bergman cyclization, proposed concurrently by Myers and Saito. This cyclization, now referred to as Myers-Saito cyclization, produces the diradical 58 that can abstract hydrogen atoms from DNA. Thus, neocarzinostatin s bioactivity is remarkably similar to calichaemicin (Figure 4.14). 

Figure 4.14 Mechanism of action of neocarzinostatin chromophore 30 Nicolaou, K. C. Dai, W.-M. Chemistry and biology of the enediyne anticancer antibiotics, Angew. Chem. Int. Ed. Engl. 1991, 30, 1387-1416. Copyright Wiley-VCH Verlag GmbH Co. KGaA. Reproduced with permission.

While these model studies have shed light on the natnre of the Myers-Saito and Schmittel cycUzations, the molecules examined bear important differences from the neocarzinostatin chromophore the chromophore is a bntadiene not an aUene the enyne-butatriene is embedded within a nine-member ring this ring is fnsed with a cyclopentane moiety and the ring bears an alcohol substitnent. 

This (7,o-diradical lacks the benzylic radical stabilization found in 61, and therefore cyclization of 68 is less exothermic than that of 59. Musch and Engels note that the Schmittel cyclization (AG (CCSD(T)/cc-pVDZ) = 18.6 kcal mol ) of 68 is favored over the Myers-Saito cyclization (AG (CCSD(T)/cc-pVDZ) = 21.1 kcal mor ). This is opposite to the case for the open chain analog 69, where the barrier for Myers-Saito cyclization is 9.7 kcal mol below the barrier for the Schmittel cyclization. However, fusing a cyclopentane ring with the eneyne-butatriene (70) favors the Myers-Saito cyclization over the Schmittel cyclization, AG (UB3LYP/6-31G(d) = 22.2 versus 22.8 kcal mol . Since neocarzinostatin chromophore follows the Myers-Saito pathway exclusively, nature has carefully balanced many factors in creating this system. 

Nuss and co-workers have demonstrated that a tandem Heck cyclization-anion capture process can access substructures related to vitamin D [58] and the neocarzinostatin chromophore (162) (Scheme 6-28) [59]. In a one-pot procedure, diiodide 159 was converted into dienediyne 160 in low yield. In this reaction, the alkyne undergoes Heck... 

The family of enediynes includes the calicheamicins, esperamycins, dynemicin A, which is not glycosylated, the C-1027 chromophore and kedarcidin (O Fig. 18 and Fig. 19). The neocarzinostatin chromophore, which does not contain an (Z)-enediyne, is also included in this family of compounds because of a similar mode of action. 

---