Systematic Exploration of the Structural Features of Yatakemycin Impacting DNA Alkylation and Biological Activity

Abstract

A systematic examination of the impact of the yatakemycin left and right subunits and their substituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extended and reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within the yatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is the unique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of its DNA alkylation reaction. This potentiates the cytotoxic activity of yatakemycin and its analogues overcoming limitations typically observed with more traditional compounds in the series (CC-1065, duocarmycins). Moreover, a study of the placement of the alkylation subunit within the three subunit arrangement (sandwiched vs extended and reversed analogues) indicates that it not only has a profound impact on the rate and efficiency of DNA alkylation but also controls and establishes the DNA alkylation selectivity as well, where both enantiomers of such sandwiched agents alkylate the same adenine sites exhibiting the same DNA alkylation selectivity independent of their absolute configuration.

Total Synthesis and Evaluation of iso-Duocarmycin SA and iso-Yatakemycin

“…The largest distinction observed between iso -duocarmycin SA and iso -yatakemycin was the altered and identical alkylation selectivity of the two enantiomers of 6 and their comparable efficiencies of DNA alkylation. This mirrors the now characteristic observations made with yatakemycin itself and related sandwiched analogues and has been discussed in detail elsewhere 23,24…”

“…Unlike the natural product and a series of yatakemycin analogues containing the DSA alkylation subunit where the two enantiomers display indistinguishable cytotoxic activity,23,24 the unnatural enantiomer of iso -yatakemycin proved ca. two-fold less active than the natural enantiomer (30 vs 15 pM) and ca.…”

“…Notably, this left-hand subunit also constitutes the central and right-hand subunits found in CC-1065, but is capped with a thiomethyl ester unique to the yatakemycin structure. The most remarkable features of this “sandwiched” three subunit arrangement are the enhanced rates and efficiencies of DNA alkylation, the near identical DNA alkylation selectivities of the two enantiomers, and their enhanced cytotoxic potency including those of the unnatural enantiomers 23,24. The synthesis of iso -yatakemycin diverged from that of iso -duocarmycin SA following chromatographic separation of the enantiomers of 22 .…”

Toxicity and repair of DNA adducts produced by the natural product yatakemycin

“…YTM, CC-1065, and the duocarmycins are extraordinarily potent antimicrobial and antitumor drugs 12 – 14 , 16 . These bulky alkylating agents preferentially bind in the deeper, narrower minor groove of AT-rich regions of DNA and undergo DNA binding-induced activation of the spirocyclopropylcyclohexadienone moiety to form covalent adducts at N 3 of adenine 17 – 21 . The resultant lesions provide a striking degree of stabilization to the DNA duplex, and have been shown to severely hinder transcription and replication 22 .…”

Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Mechanistically, this selective DNA alkylation is achieved through the forced adoption of a helical conformation upon binding to the minor-groove AT-rich regions of DNA, which disrupts the stabilizing vinylogous amide and activates the cyclopropane for nucleophilic attack. 19,20 These natural products are not clinically viable due to either severe adverse events, including lethal hepatotoxicity and extreme myelotoxicity, or a lack of in vivo activity.…”