Chemistry and Biology of the Enediyne Anticancer Antibiotics

Abstract

Novel, biologically active substances from nature often provide excitement, stimulation, challenges, and opportunities for the scientific and medical communities. Experience and wisdom dictate investigation of their chemistry and pursuit of their chemical synthesis for more often than not, the rewards for both chemistry and medicine are great. The enediyne anticancer antibiotics are a rapidly emerging class of such compounds derived from bacterial sources. Combining unprecedented and highly unusual molecular architecture, phenomenal biological activities and fascinating modes of action, these DNA cleaving compounds burst onto the scene in the latter half of the 1980s when their structures became known, and they rapidly moved to center stage. Today the enediyne family includes the neocarzinostatin chromophore, the calicheamicins, the esperamicins, and the dynemicins, and soon the number of family members is certain to increase. These molecules elicited extensive research activities in chemical, biological, and biomedical circles and inspired the design of a number of novel molecular assemblies to probe and mimic their chemical and biological actions. A new body of synthetic technology and several novel synthetic strategies have already been devised to address the challenges posed by these molecules, and several new DNA cleaving agents have been designed and synthesized. This article summarizes the chemistry and biology of the enediynes and discusses mechanistic, synthetic, molecular design, and DNA cleavage aspects associated with the field.

ATP-triggered anticancer drug delivery

“…We anticipate that this strategy will provide new opportunities for utilizing ATP as a metabolic trigger, which can lead to the development of increasingly specific DDS. Here Dox was intercalated in the GC-rich pairs of the DNA motif; however, other drugs [51][52][53] could also be loaded into the DNA chain through their specific affinity and be released by ATP's invasion. Alternatively, drugs can be encapsulated into nanocarriers 'caged' by ATP aptamer for reversibly controlling drug release on ATP's trigger.…”

Identification of the adduct between a 4-aza-3-ene-1,6-diyne and DNA using electrospray ionization mass spectrometry

“…Currently, nearly twenty of these natural enediynes have been identified, including calichemicin ␥ 1 I [6,7], dynemicin [8], and the esperamicins [9,10]. While these enediynes offer extremely high cytotoxic activities, their clinical use as anti-tumor agents has been limited due to their delayed activities and general toxicity [2][3][4][5].To overcome the shortcomings of these natural enediynes, a range of synthetic analogs have been explored [3,11], each with the goal of improved properties for clinical use. While still capable of cleaving DNA like the natural products through cycloaromatization reactions and subsequent hydride abstraction by the diradical intermediate [2-4, 11, 12], these analogs offer potential advantages, such as more controlled activation of the compound in vivo [13][14][15][16][17][18][19][20][21][22][23] or increased selectivity for tumor cells [24 -30].…”

“…Currently, nearly twenty of these natural enediynes have been identified, including calichemicin ␥ 1 I [6,7], dynemicin [8], and the esperamicins [9,10]. While these enediynes offer extremely high cytotoxic activities, their clinical use as anti-tumor agents has been limited due to their delayed activities and general toxicity [2][3][4][5].…”

Two [7.3.1]Azabicyclo-z-3-ene-1,5-diyne Analogues of Dynemicin A

“…The C9--N10---C19----O20 torsion angle is 11.7 (2) ° for molecule A and 179. 2C19H15NO4.0.5C4HsO2 AND C28H27NO4.0.5C4HsO2 (C3...C8) is related to the ease of cycloaromatization (Nicolau & Dai, 1991). For compound (1), the C3...C8 distance is 3.416 (3) and 3.440 (3)/~ for molecules A and B, respectively.…”