Ri-Zhen Huang

Combretastatin A-4 Analogue: A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV) Moiety with a Unique Mode of Action.

Three new Pt(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex 13, which was attached to an inhibitor of tubulin at one axial position of Pt(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex 13 has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin.

Anticancer Platinum(IV) Prodrugs Containing Monoaminophosphonate Ester as a Targeting Group Inhibit Matrix Metalloproteinases and Reverse Multidrug Resistance

A novel class of platinum(IV) complexes comprising a monoaminophosphonate ester moiety, which can not only act as a bone-targeting group but also inhibit matrix metalloproteinases (MMPs), were designed and synthesized. Biological assay of these compounds showed that they had potent antitumor activities against the tested cancer cell lines compared with cisplatin and oxaliplatin and indicated low cytotoxicity to human normal liver cells. Particularly, the platinum(IV) complexes were very sensitive to cisplatin resistant cancer cell lines. The corresponding structure-activity relationships were studied and discussed. Related mechanism study revealed that the typical complex 11 caused cell cycle arrest at S phase and induced apoptosis in Bel-7404 cells via a mitochondrial-dependent apoptosis pathway. Moreover, complex 11 had potent ability to inhibit the tumor growth in the NCI-H460 xenograft model comparable to cisplatin.

Antitumor lignanamides from the aerial parts of Corydalis saxicola

BACKGROUND Cancer is one of the leading cause of unnatural death globally. There is still a great need for effective anticancer agents from plant sources. Corydalis saxicola Bunting is a medicinal plant that is traditionally used to treat various diseases in southwest China. Previous phytochemical investigations of C. saxicola have focused on isoquinoline alkaloids that have been isolated, which have activity against anti-hepatitis B virus and inhibit DNA topoisomerase I. However, the exploration of other classes of constituents and their bioactivities needs further study. PURPOSE The aim of this study was to investigate the antitumor activity of isolated lignanamides as well as their detailed cellular proliferation, suppression, and cytotoxic mechanisms. METHODS Herbs were extracted and constituents were purified by chromatographic separation, including silica gel, ODS, MCI, Sephadex LH-20 and Preparative HPLC. The compound structures were elucidated by the use of UV, IR, NMR and MS spectral data. The cytotoxicity effects of all compounds from the MGC-803, HepG2, T24, NCI-H460, Spca-2, and HL-7702 cell lines were studied by MTT assays. The induction of apoptosis by corydalisin C was investigated using acridine orange/ethidium bromide staining, Hoechst 33,258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry. RESULTS Three new lignanamides, together with five known analogues, were isolated from the aerial parts of C. saxicola. Corydalisin C possessed the most potent inhibitory effects, with an IC50 value of 8.81 ± 2.05µM against MGC-803 cells. SAR analysis showed that the sterics and chirality of lignanamides play a crucial role in pharmacologically relevant events. The antitumor activity was possibly due to the induction of cell apoptosis. Western blot experiments demonstrated that corydalisin C may induce apoptosis through both intrinsic and extrinsic apoptosis pathways, accompanied by down-regulating the expression of Bcl-2 and FasL in a time-dependent manner. CONCLUSION This study provides evidence that a lignanamide from the ethyl acetate extract of whole plants of C. saxicola showing potential in cancer treatment.

Platinum(IV) complexes conjugated with phenstatin analogue as inhibitors of microtubule polymerization and reverser of multidrug resistance

Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively. Mechanism study suggested that complex 10 induced cell-cycle arrest at the G2/M phase and caused apoptotic cell death of human lung cancer NCI-H460 cells through the mitochondrial mediated pathway. Moreover, complex 10 effectively inhibited the tumor growth in the NCI-H460 xenograft model.

4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies

BACKGROUND Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties. OBJECTIVE In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs. METHOD Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR. RESULTS Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-κB (NF-κB) activity and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1. CONCLUSION Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.

Dual-targeting antitumor hybrids derived from Pt(IV) species and millepachine analogues

Many strategies have been developed to circumvent the shortcomings of Pt(II)-based chemotherapy, but the inherent problems still have not been effectively resolved. Here we report a new series of dual-targeting Pt(IV) prodrugs, conjugates of millepachine analogues with the related Pt(IV) complexes derived from cisplatin or oxaliplatin, respectively, which can inhibit tubulin polymerization and induce DNA damage. Among them, compound 19 possessed excellent antitumor activities against the tested human cancer cell lines, and arrested the cell cycle at the G2/M phases and ultimately induced cell apoptosis. Interestingly, its low cytotoxicity toward two human normal cells and sensitivity toward two cisplatin-resistant cells revealed the possibility for cancer therapy. More importantly, 19 displayed excellent antitumor efficacy in the SK-OV-3 xenograft model better than cisplatin and the corresponding millepachine analogue. Our research provided an efficient strategy for multi-targeting antitumor drug development.

Discovery of 18β-glycyrrhetinic acid conjugated aminobenzothiazole derivatives as Hsp90-Cdc37 interaction disruptors that inhibit cell migration and reverse drug resistance

A series of 18β-glycyrrhetinic acid (GA) conjugated aminobenzothiazole derivatives were designed, synthesized and evaluated for disruption activity of Hsp90-Cdc37 as well as the effects of in vitro cell migration. These compounds exhibited relatively good disruption activity against Hsp90-Cdc37 with IC50 values in low micromolar range. A docking study of the most active compound 11g revealed key interactions between 11g and Hsp90-Cdc37 complex in which the benzothiazole moiety and the amine chain group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU and showed potent suppression activity against drug-resistant cancer cells. In particular, compound 11 g appeared to be the most potent compound against the A549 cell line, at least partly, by inhibition of the activity of Hsp90 and apoptosis induction. The treatment of A549 cells with compound 11g resulted in inhibition of in vitro cell migration through wound healing assay and S phase of cell cycle arrested. In addition, 11g-induced apoptosis was significantly facilitated in A549 cells. Thus, we conclude that GA aminobenzothiazole derivatives may be the potential Hsp90-Cdc37 disruptors with the ability to suppress cells migration and reversed drug-resistant.

Synthesis and biological evaluation of terminal functionalized thiourea-containing dipeptides as antitumor agents

A series of antitumor agents based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for antiproliferative activity using a panel of cancer cell lines, and the effects and mechanism of apoptosis induction were determined. These compounds exhibited significant selectivity to different cancer cell lines with IC50 values at micromolar concentrations. In particular, compound I-11 appeared to be the most potent compound, with an IC50 = 4.85 ± 1.44 μM against the NCI-H460 cell line, at least partly, by the induction of apoptosis. Mechanistically, compound I-11 induced the activation of caspase-12 and CHOP, which triggered apoptotic signalling via the ROS-dependent endoplasmic reticulum pathway and arrested the cell cycle at the S phase. Thus, we concluded that dipeptide derivatives containing the thiourea moiety terminally functionalized by electron-withdrawing substituents may be potential antitumor agents for further investigation.

Three new C-27-carboxylated-lupane-triterpenoid derivatives from Potentilla discolor Bunge and their in vitro antitumor activities

Three new lupane-triterpenoids (1–3) along with six known compounds (4–9) were isolated from the ethanolic extract of whole plant of Potentilla discolor Bunge. The structures of Compounds 1–3 were established by extensive 1D and 2D NMR together with other spectrum analysis, indicating that their C-27 positions were highly oxygenated, which were rarely found in nature. Their in vitro anti-proliferative activities against HepG-2, MCF-7 and T-84 cell lines were evaluated by Cell Counting Kit-8 (CCK-8) assay, and the results showed different activities for three cell lines with IC50 values ranging from 17.84 to 40.64 μM. In addition, the results from Hoechst 33258 and AO/EB staining as well as annexinV-FITC assays exhibited Compound 1 caused a markedly increased HepG-2 cellular apoptosis in a dose-dependent manner. The further mechanisms of Compound 1-induced cellular apoptosis were confirmed that 1 induced the production of ROS and the alteration of pro- and anti-apoptotic proteins, which led to the dysfunction of mitochondria and activation of caspase-9 and caspase-3 and finally caused cellular apoptosis. These results would be useful in search for new potential antitumor agents and for developing semisynthetic lupane-triterpenoid derivatives with high antitumor activity.

Selagintamarlin A: A Selaginellin Analogue Possessing a 1H-2-Benzopyran Core from Selaginella tamariscina

Selagintamarlin A (1), a novel selaginellin analogue featuring the unique motif of 1H-2-benzopyran, a new selaginpulvilin E (2), together with eight known analogues were isolated from Selaginella tamariscina. Their structures were elucidated by extensive spectroscopic analyses. A plausible biosynthetic pathway of 1 was also postulated. Compound 1 showed remarkable inhibitory activity against phosphodiesterase-4 (PDE4D2), with an IC50 value of 40 nM, which is 20-fold higher than that of the positive control (rolipram). Furthermore, compound 1 significantly inhibited tubulin polymerization.