Dynemicin A
Dynemicin A is an anti-cancer enediyne drug that has shown promise for cancer treatments but still requires further research[1]. It was first isolated from the soil in the Gujarat State of India and is a natural product of the indigenous bacteria Micromonospora chersina[1]. The compound displays a bright purple color due to the anthraquinone chromophore structure within it and was initially isolated for its aesthetic properties as a dye until further research demonstrated its anti-cancer properties[1].
The Bristol-Myers Pharmaceutical Company elucidated the structure in Japan using X-ray diffraction studies of a closely related compound[1]. The first reported chemical synthesis of dynemicin was accomplished by Myers and coworkers[1]. Dynemicin A is an antitumor natural product isolated from Micromonospora chersina which causes DNA strand cleavage[1]. Iwasaki et al. first studied the biosynthetic pathway of Dynemicin A by 13C NMR labeling experiments[1].
Dynemicin A is thought to be biosynthesized separately from two different heptaketide chains originated from seven head-to-tail condensations, which is then connected to form Dynemicin A[1]. Initially, precursors such as 3 and 4 were proposed to derive from the oleate/crepenynate pathway, as initially put forth for NSC Chrom A biosynthesis[1]. However, recent work by Thorson and coworkers revealed the biosynthesis of the dynemicin enediyne core to be catalyzed by an enediyne polyketide synthase (PKS)[4].
Dynemicin A is specific for B-DNA, and functions by intercalating into the minor groove of the double helix[1]. For intercalation to occur, the separation between strands, which is usually 3-4 angstroms, needs to be widened to 7-8 angstroms to allow enough space for the ligand to bind[1]. Given this, the DNA must be strained to accommodate the Dynemicin A, resulting in an induced fit-like process[1]. Once intercalated within the DNA, the epoxide is activated in one of two ways[1]. First, if NADPH or a thiol reduces the molecule, the Bergman re-cyclization of the enediyne proceeds[1]. Second, if a nucleophilic mechanism is utilized, then the retro-Bergman re-cyclization of the enediyne proceeds[1].
A multistep route for the preparation of enantiomerically pure, synthetic dynemicin A was developed, and the absolute configuration of natural dynemicin was determined by comparing the synthetic drug with dynemicin A derived from fermentation[2]. The route that was developed is highly convergent, as the result of a late-stage coupling reaction that combines two complex synthetic fragments, and has been shown to provide access to non-natural dynemicins of wide structural variability by modifications of these fragments[2]. In this way, several nonnatural dynemicins, unavailable by any other means, were synthesized and shown to have DNA-cleaving activity in the presence of glutathione or NADPH[2].
Dynemicin A is a member of a subfamily of enediyne antitumour antibiotics characterized by a 10-membered carbocycle fused to an anthraquinone, both of polyketide origin[4]. Sequencing of the dynemicin biosynthetic gene cluster in Micromonospora chersina previously identified an enediyne polyketide synthase (PKS), but no anthraquinone PKS, suggesting gene(s) for biosynthesis of the latter were distant from the core dynemicin cluster[4]. To identify these gene(s), the genome of M. chersina was sequenced and analyzed, producing a short list of putative PKS candidates, yet CRISPR-Cas9 mutants of each locus retained dynemicin production[4]. Subsequently, deletion of two cytochromes P450 in the dynemicin cluster suggested that the dynemicin enediyne PKS, DynE8, may biosynthesize the anthraquinone[4]. Together with 18O-labelling studies, evidence was presented that DynE8 produces the core scaffolds of both the enediyne and anthraquinone, and a working model was provided to account for their formation from the programmed octaketide of the enediyne PKS[4].
Citations:
[1] https://en.wikipedia.org/wiki/Dynemicin_A
[2] https://pubmed.ncbi.nlm.nih.gov/9383401/
[3] https://www.jstage.jst.go.jp/article/antibiotics1968/42/9/42_9_1449/_article
[4] https://www.nature.com/articles/nchem.2876
[5] https://pubs.acs.org/doi/10.1021/ja960040w