FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar KD for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7(8H)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G0/G1 cell cycle arrest and apoptosis in AML cells. In in vivo studies, 31 significantly suppresses the tumor growth in MV4–11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment.

•Novel metal complexes of naphthalimide–cyclam conjugates were designed, synthesized.•All of the compounds were evaluated of their antitumor activities.•Zn(II) and Cr(III) complexes displayed as multi-target RTK inhibitors.•Representative compound 8a showed antiproliferative and antiangiogenic activities.A novel series of metal complexes of naphthalimide–cyclam conjugates were synthesized and their in vitro antitumor activities were evaluated. The newly-synthesized compounds showed huge diversity of antiproliferative potency due to variety of metal ions and length of alkyl chains, among which the Zn(II) and Cr(III) complexes exhibited comparable antiproliferative activities with amonafide via multiple tyrosine kinase inhibition. Further research revealed that the representative compound 8a displayed broad-spectrum antiproliferative activity against 15 cancer cell lines with average IC50 value 10.18 ± 3.25 μM, and effective antiangiogenic activity on human microvascular endothelial cells (HMEC-1). In brief, metal complexes of naphthalimide–cyclam conjugates were firstly designed and synthesized as multi-target tyrosine kinase inhibitors and proved of their antitumor capacities.A novel series of metal complexes of naphthalimide–cyclam conjugates were designed and synthesized, which displayed as multi-target RTK inhibitors. Representative compound 8a exhibited both broad-spectrum antiproliferative capacity and antiangiogenic activity.

•Novel naphthalimide derivatives were synthesized.•The compounds were topo II inhibitors and showed good antiproliferative activity.•For the first time, naphthalimides were proved to be tyrosine kinase inhibitors.•8d displayed effective antiangiogentic activity by inhibiting tyrosine kinases.Novel naphthalimide derivatives were designed and synthesized to modulate both topoisomerase II (topo II) and receptor tyrosine kinases (RTKs). Most target compounds exhibited effective and selective antiproliferative activities against three cancer cell lines by inhibiting topo II. The IC50 values ranged from 1.5 to 19.1 μM. Moreover, compounds 8d and 12d moderately inhibited various angiogenesis-related RTKs, including FGFR1, VEGFR2 and PDGFRα. The representative compound 8d was then proved to possess antiangiogenic activity, which was evidenced by the inhibition of migration and tube formation activities of HMEC-1 cells. To our knowledge, it is the first time naphthalimides were identified as tyrosine kinases inhibitors (TKIs) besides their conventional cytotoxicity.A novel series of naphthalimides were synthesized. Several of them could inhibit both topo II and angiogenesis-related receptor tyrosine kinases. The representative compound 8d not only was potent antiproliferative agent, but also exhibited effective antiangiogenic activity at 10 μM

Three series of novel oxo-heterocyclic fused naphthalimide derivatives (8a–8f, 13a–13d, 17a–17d) were prepared. The newly-synthesized compounds, and their thio-heterocyclic fused analogs (1a–1c, 2a–2d, 3a–3c) exhibited potent antiproliferative activity correlated well with their structure. Further research demonstrated that all the representative compounds 13a, 2a and 17a, 3a showed strong inhibition activity to topo II similarly with amonafide, and also potent topo I inhibition activity, which was seldom reported before for naphthalimide derivatives. Preliminary exploration proved their DNA sequence preference. In all, dual topo I/topo II inhibition and DNA sequence preference might contribute to enhancing tumor selectivity and overcoming drug resistance.Three series of oxo-heterocyclic fused naphthalimides were prepared. The relatively weak DNA intercalators were potent dual topo I/topo II inhibitors.Highlights► Novel oxo-heterocyclic fused naphthalimides were synthesized. ► Potent antiproliferative activities and preliminary SAR were observed. ► Naphthalimides are proved to be dual topo I/II inhibitors.