Shaoying Tan

A New Class of Naphthalimide-Based Antitumor Agents That Inhibit Topoisomerase II and Induce Lysosomal Membrane Permeabilization and Apoptosis

Based on the advantages of multitarget drugs for cancer treatment, a new class of naphthalimides was designed, synthesized, and proved to inhibit topoisomerase II (topo II), induced lysosomal membrane permeabilization (LMP), and ultimately caused apoptosis and cell death. The majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC(50) values ranging from 2 to 10 microM and are more active than amonafide, a naphthalimide that was in phase III clinical trials. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topo II inhibitors. Furthermore, compounds 7b-d were found to notably induce LMP and exhibited better antiproliferative activity compared with their single-target analogues. All of the newly synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.

Acenaphtho[1,2-b]pyrrole-based selective fibroblast growth factor receptors 1 (FGFR1) inhibitors: design, synthesis, and biological activity.

A novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target prediction revealed that tyrosine kinases might be the potential targets of the representative compound 2, which was subsequently validated by enzyme-linked immunosorbent assay (ELISA) for its selective and active FGFR1 inhibition of various tyrosine kinases. The structure-activity relationship (SAR) analysis aided by molecular docking simulation in the ATP-binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2-5) are potent inhibitors of FGFR1 with IC(50) values ranging from 19 to 77 nM. Furthermore, these compounds exhibited favorable growth inhibition property against FGFR-expressing cancer cell lines with IC(50) values ranging from micromolar to submicromolar. Western blotting analysis showed that compounds 2, 3, and 2b inhibited activation of FGFR1 and extracellular-signal regulated kinase 1/2 (Erk1/2).

Oxo-heterocyclic fused naphthalimides as antitumor agents: synthesis and biological evaluation.

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.

Naphthalimides exhibit in vitro antiproliferative and antiangiogenic activities by inhibiting both topoisomerase II (topo II) and receptor tyrosine kinases (RTKs)

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.

Antiproliferative and apoptosis-inducing activities of novel naphthalimide–cyclam conjugates through dual topoisomerase (topo) I/II inhibition

A novel series of naphthalimide-cyclam conjugates were designed and synthesized. Among them, compounds 4c, 4d, 8c and 8d which bearing long lipophilic alkyl chains, displayed comparable or more potent cytotoxic activities against human tumor cell lines than amonafide. Furthermore, the four compounds were proved to possess strong inhibition against both topoisomerase I and II. The representative compound 8c exhibited moderate DNA intercalation activity. Molecular modeling studies identified the possible interaction of compound 8c with the molecular target by forming topoisomerase/DNA/drug ternary complex. Finally, derivatives with long lipophilic alkyl chains could efficiently induce apoptosis.

3B, a novel photosensitizer, inhibits glycolysis and inflammation via miR-155-5p and breaks the JAK/STAT3/SOCS1 feedback loop in human breast cancer cells.

Compared to normal cells, most cancer cells produce ATP by glycolysis under aerobic conditions rather than via the tricarboxylic acid cycle (TCA). This study is intended to determine whether 3B, a novel photosensitizer, can inhibit glycolysis and inflammation in breast cancer cells. We showed that 3B had the ability to repress glucose consumption as well as the generation of ATP, lactate and lactate dehydrogenase. 3B-PDT not only inhibited the expression of IL-1β and IL-6 but also affected the JAK-STAT3 inflammatory pathway in vitro. The present study showed that 3B featured a significant inhibitory effect on the expression of microRNA-155-5p and SOCS1 might serve as a target gene. In vivo studies revealed that 3B inhibited tumor growth and exhibited almost no side effects. Therefore, through the anti-glycolytic effect and breakage of the JAK/STAT3/SOCS1 feedback loop via miR-155-5p, 3B may potentially serve as a potential therapeutic agent against breast cancer.

One small molecule as a theranostic agent: naphthalimide dye for subcellular fluorescence localization and photodynamic therapy in vivo

A novel single and small molecular theranostic agent (1a) based on a naphthalimide dye has been developed and characterized. The agent (1a) displays excellent fluorescence for cell imaging (fluorescent quantum yields of 0.81) and photodynamic effects for therapeutic effectiveness (micromolar inhibition efficacy in vitro towards a broad spectrum of tumor models and anticancer treatment in vivo on A375 tumor xenograft models). This provides a new approach for simultaneous improvement in two directions using a small molecule as theranostic agent, which usually are in conflict with each other for most traditional theranostic agents.