Minor distamycin

A+T-rich distamycin ss cuts, from minor ) distamycin- 82S6,... 

Nature provides examples of sequence-selective minor groove binding, such as antibiotics including netropsin, distamycin, anthelvencin, and kikumycin. 

Some of the best characterized ligands that bind in the minor groove of DNA are distamycin and netropsin. Both these molecules are long and flat and are sterically and electrostatically complementary to the characteristics of the minor groove of DNA. Distamycin and netropsin are known to have specific affinity towards the minor groove of AT rich regions of B-DNA. 

The electrostatic potential calculations have shown that the minor groove of AT rich B-DNA sequence has the lowest negative potential.15 This led to the implication that the cationic drugs will exhibit binding specificity to the minor groove regions of AT rich sequences. The crystal structure of a DNA distamycin complex showed that there is only one molecule bound to the minor groove of an AATT DNA site.2 However, experimental studies... 

Fitzgerald DJ, Anderson JN (1999) Selective nucleosome disruption by drugs that bind in the minor groove of DNA. J Biol Chem 274(38) 27128-27138 Fox KR, Cons BM (1993) Interaction of mithramycin with DNA fragments complexed with nucleosome core particles comparison with distamycin and echinomycin. Biochemistry. 32(28) 7162—7171 Friedman HS, Kerby T, Calvert, H (2000) Temozolomide and treatment of malignant gliomas. CUn Cancer Res 6 2585-2597... 

Distamycin A (178) Antibiotic Brostallicin (PNU- Oncology DNA minor groove Phase II Cell Therapeutics 870-877... 

The synthesis of a pyrrole segment common to netropsin and distamycin is shown in Scheme 2ji°l Friedel-Crafts acylation of 1-methylpyrrole (1) followed by nitration at C4 provides 3 in 54% yield. After a haloform reaction, hydrogenolysis, N-protection with B0C2O, and saponification, the pyrrolecarboxylic derivative acid 7 was obtained in 30% overall yield from 3. This monomer is readily chain-extended to the pyrrole-imidazole derivative 9 (Scheme 3)J10 Furthermore, solid-phase synthesis with this and related pyrrole-containing building blocks leads to polyamides that have recently been used in the recognition of a 16 base-pair sequence in the minor groove of DNA.1" ... 

Design, synthesis, and biological evaluation of DNA minor-groove binders, ligands structurally related to CC-1065, distamycin, and anthramycin 03PAC187. 

In the search for simpler analogues of netropsine and distamycin A, which are DNA minor groove binding antibiotics, pyrazoles (316) and (317) have been synthesized <89JOC428). The x-ray structure of (316) was reported. 

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