Structural and conformational features relevant to the anti‐tumor activity of calicheamicin γ

Abstract

The structural and conformational features of the potent 10-membered enediyne-containing calicheamicin γ 1I that account for its remarkable DNA site-specific binding and cleavage are reviewed. A variety of spectroscopic and biophysical techniques were used to gain insight into the binding and stereospecific DNA cleavage of this potent antitumor agent. These include gel-shift cleavage assays, atom transfer NMR experiments, drug-DNA conformational studies, circular dichroism, and capillary electrophoresis. Computational descriptions are described for the DNA binding and cleavage of calicheamicin and its activated transient intermediates based on density functional and molecular mechanics calculations. In addition, the structure and clinical utility of calicheamicin immunoconjugates for antibody-targeted chemotherapy is presented.

In Vivo Biotransformations of Antibody–Drug Conjugates

“…Gemtuzumab ozogamicin (Mylotarg), the first marketed ADC, and more recently inotuzumab ozogamicin (CMC-544), in late clinical development [54], contain derivatives of the natural product calicheamicin [55]. This payload is an enediyne-containing molecule that binds to the minor groove of DNA in a sequence selective manner and subsequently undergoes a so-called 'Bergman cyclization' resulting in a diradical which drives DNA double-strand scission [56].…”

Enediynes, enyne‐allenes, their reactions, and beyond

“…They are masterpieces, designed by nature to protect microorganisms against toxic bacteria and viruses. Natural enediynes show potent antibiotic and antitumor activities with a cytotoxicity comparable to or even higher than that of any known microbial metabolite . Up to date, ca.…”

“…9‐membered ring enediynes (see, e.g., molecules 23 – 29 in Table and Figure (a)) are highly strained, and therefore are only stable if they are bound to an apoprotein . While enediynes incorporated in a 10‐membered ring are stable enough to be isolated, the 9‐membered ring enediynes without apoprotein undergo spontaneous cycloaromatization leading to the exclusive isolation of aromatized derivatives . This applies to neocarzinostatin ( 23 ), C‐1027 ( 24 ), maduropeptin ( 25 ), kedarcidin ( 26 ), and the precursors of sporolides ( 28 ) and cynaosporasides ( 29 ).…”

Novel insights on the DNA interaction of calicheamicin γ1I

“…Behind the great significance that their work represented for the whole chemistry community, an additional value of their efforts derived from the synthesis of defined Cal fragments (in particular the carbohydrate tail and the enediyne containing moiety) as well as of several derivatives. It was the critical use of these compounds in controlled experimental conditions that provided the actual available knowledge of the mechanism that this molecular machine uses to bind and cleave DNA in a such concerted and efficient fashion . In the hand of expert molecular biologists, chemists and biophysics, these synthetic products allowed to exactly map the interaction site and to confirm that the carbohydrate tail of Cal is able to recognize the same sequences as the whole drug .…”

“…It was the critical use of these compounds in controlled experimental conditions that provided the actual available knowledge of the mechanism that this molecular machine uses to bind and cleave DNA in a such concerted and efficient fashion. 18 In the hand of expert molecular biologists, chemists and biophysics, these synthetic products allowed to exactly map the interaction site [19][20][21] and to confirm that the carbohydrate tail of Cal is able to recognize the same sequences as the whole drug. 22 At the same time, Cal was found to exhibit a higher DNA binding affinity when compared to its carbohydrate derivative thus supporting an active interaction of the aglycone with the nucleic acid.…”