We designed a conjugated compound by coupling temozolomide (TMZ) with doxorubicin (DOX) via an acylhydrazone linkage as a potential prodrug used for glioblastoma multiforme (GBM) treatment. Viscosity and spectroscopic studies revealed that the drug conjugate could act as a nonclassical double intercalating agent. Although free TMZ is an inefficient DNA binder in comparison to DOX, the TMZ moiety interacted with DNA as an induced intercalator, arising from the synergistic effect of DOX moiety that mediated conformational changes of the DNA helix. Two binding modes were proposed to interpret the double intercalating effect of the drug conjugate on intra-and inter-DNA interactions that could cause DNA cross-linking and fibril aggregates. We also developed a delivery nanoplatform with a loading efficiency of 83% using copper-bound apoferritin as a nanocarrier. In sharp contrast to the short half-life of free TMZ, the nanocomposite was stable under physiological conditions without detectable drug decomposition after a 2 week storage, and drug release was activatable in the presence of glutathione at millimolar levels. The antitumor effect of the drug conjugate and nanocomposite against GBM cells was reported to demonstrate the potential therapeutic applications of double intercalating materials.

Environment-responsive in situ synthesis of molecular fluorescent dyes is challenging. Herein, we develop a photoextension strategy to make trimethine cyanines with decent conversion efficiency (up to 81 %) using 1-butyl 2,3,3-trimethyl 3H-indole derivatives as the sole precursors, and demonstrate a free radical mechanism. In the inducer-extension stage, free radicals and reactive oxygen species (ROS) were able to mediate similar reactions with no assistance of light. We explored a Mito-extension strategy to in situ synthesize trimethine cyanines in the living cells. The cellular ROS-dependence provided a foundation for preferential cyanine expression in cancer cells. Finally, we applied an iodized precursor as an intrinsic ROS-activated theranostic agent that integrated mitochondria-targeted cyanine synthesis, cell imaging and phototherapy.

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Fms-like receptor tyrosine kinase 3 (FLT3) has been emerging as an attractive target for the treatment of acute myeloid leukemia (AML). By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1H-pyrazole-3-carboxamide derivatives were designed and synthesized. Compound 8t showed strong activity against FLT3 (IC50: 0.089 nM) and CDK2/4 (IC50: 0.719/0.770 nM), which is more efficient than FN-1501(FLT3, IC50: 2.33 nM; CDK2/4, IC50: 1.02/0.39 nM). Compound 8t also showed excellent inhibitory activity against a variety of FLT3 mutants (IC50 < 5 nM), and potent anti-proliferative effect within the nanomolar range on acute myeloid leukemia (MV4-11, IC50: 1.22 nM). In addition, compound 8t significantly inhibited the proliferation of most human cell lines of NCI60 (GI50 < 1 μM for most cell lines). Taken together, these results demonstrated the potential of 8t as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics.