We describe several
new aromatic nitrogen mustards with various
aromatic substituents and boronic esters that can be activated with
H2O2 to efficiently cross-link DNA. In vitro
studies demonstrated the anticancer potential of these compounds at
lower concentrations than those of other clinically used chemotherapeutics,
such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic
toward breast cancer and leukemia cells that have inherently high
levels of reactive oxygen species. Importantly, 10 was
10–14-fold more efficacious than melphalan and chlorambucil
for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells
than either chlorambucil or the lead compound, 9. The
introduction of an amino acid side chain improved the solubility and
permeability of 10. Furthermore, 10 inhibited
the growth of TNBC tumors in xenografted mice without obvious signs
of general toxicity, making this compound an ideal drug candidate
for clinical development.
A coumarin-modified pyrimidine nucleoside (1) has been synthesized using Cu(I)-catalyzed click reaction and incorporated into oligodeoxynucleotides (ODNs). Interstrand cross-links are produced upon irradiation of ODN containing 1 at 350 nm. Cross-linking occurs via [2+2] cycloaddition reaction with the opposing thymidine, 2′-deoxycytidine, or 2′-deoxyadenosine. A much higher reactivity was observed with dT than dC or dA. Irradiation of the dT-1 and dC-1 cross-linked products at 254 nm leads to a reversible ring-opening reaction, while such phenomenon was not observed with dA-1 adducts. The reversible reaction is ultrafast and complete within 50 s – 90 s. Consistent photoswitching behavior was observed over 6 cycles of irradiation at 350 nm and 254 nm. To the best of our knowledge, this is the first example of photoswitchable interstrand cross-linking formation induced by a modified pyrimidine nucleoside. Compound 1 is a novel tool for developing reversible DNA photoswitches which will lead to new applications in chemistry, biology, and nanotechnology.
Two nitroimidazole modified thymidines 1a and 1b have been synthesized and incorporated into DNA oligomers. The 350 nm photolysis of 1a and 1b generated a 5-(2′-deoxyuridinyl)methyl radical that induced DNA interstrand cross-links (ICL). Higher ICL yield was observed under hypoxic conditions than aerobic conditions. The photoproducts of monomers or DNA oligomers were isolated and characterized by NMR and/or mass spectroscopy.
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