Synthetic and Mechanistic Studies on the Azabicyclo[7.3.1]enediyne Core and Naphtho[2,3-h]quinoline Portions of Dynemicin A

Abstract

The synthesis of the 13-keto-10-azabicyclo[7.3.1]enediyne core structure of dynemicin A has been achieved by two routes, Schemes and . The chemistry of the 13-keto core structure is dominated by the unusually facile bridgehead enolization. Comparison of the rates of cycloaromatization of a variety of enediynes revealed that substantial rate differences occurred even though the distance between the bonding acetylenes was virtually identical. A non-radical cycloaromatization pathway, initiated by thiol addition to the enediyne system, was discovered, and the simple core amine 26 exhibits modest in vitro and in vivo antitumor activity. Finally, two methods for the synthesis of the naphtho[2,3-h]quinoline portion of dynemicin A are described, and both these compounds also exhibit antitumor activity.

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

“…[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.…”

The Nicholas Approach to Natural Product Hybrids

“…v)ammonium nitrate (CAN) [17] or I 2 . [18] In all cases, a gHMBC cross peak is observed between H-3 of the bpinene fragment (17: d H 4.59) and the carbon of the nucleophile attached to the terpene (17: d C 113.8).…”

Alkoxy and Enediyne Derivatives Containing 1,4-Benzoquinone Subunits—Synthesis and Antitumor Activity

“…These compounds affect the DNA cleavage on two difference routes, directly by reduction of the anthraquinone ring and opening of the epoxide ring and indirectly by the formation of a highly reactive 1,4-diradical intermediate from the ( Z )-enediyne group [ 18 , 19 , 20 ]. Thereby, natural conjugates of the enediyne ring and the 1,4-benzoquinone subunit show high activity against Gram-positive and Gram-negative bacteria and antitumor activity against a broad spectrum of human and murine cancer cell lines [ 2 , 3 , 17 , 21 , 22 , 23 ]. Unlike the other enediyne antibiotics, dynemicin A exhibits low toxicity [ 22 , 23 ].…”