TELOMERASE: A NOVEL TARGET OF ANTITUMOR AGENTS

Telomerase activity was found to be high in various human cancers, but absent in most normal tissues. Its expression pattern made it a novel target for antitumor agents. Several strategies against telomerase were presented in this review. Targeting the telomerase RNA component by oligonucleotide/ribozyme was considered to be one of the most hopeful approaches. Some progresses were made in this area, such as the use of PANs and 2–5A antisense compounds. The relationships among telomerase activity and cell differentiation, signal transduction, oncogene, tumor suppressor gene as well as cell cycle modulation also provided a series of valuable ideas in designing anti-telomerase drugs for cancer therapy. In conclusion, although there is still a long way in understanding the mechanism and regulation of telomerase, the advance of studies on telomerase has allowed the development of numerous strategies for the treatment of cancer.

Cation-anionicpalladium Complexes—New Types of Antitumor, Immune Response-modulating and Radioprotective Agents

Here we report results of our investigations of new class of bioactive palladium compounds (AH n ) m [PdCl 4 ], which were discovered as a result of systematic study of correlations between composition, structure and bioactivity of different types of platinum metals coordination compounds. For the first time we demonstrated in vivoa possibility of development of palladium compounds, which exceed cisplatin in antitumor activity and do not show immunosuppressive effects, and palladium compounds with immunostimulating and radioprotective activities. Combinations of cytostatic agents or radiation with palladium complexes lead to significant synergism of their activities and high therapeutic efficiency exceeded an efficiency of their separated use.

Design,Synthesis and Biological Activities of Quinazoline Containing Sorafenib Analogs as Antitumor Agents

A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the synthesized compounds showed significant cytotoxicity against the selected cell lines. These cytotoxicities were consistent with their inhibitory activity against the phosphorylation of c-Raf, MEK1/2 and ERK1/2. Compound GD-09 also showed much stronger anti-tumor activity than that of sorafenib in vivo by B16 melanoma xenograft model test.

Design and Synthesis of Hydrazine and Oxadiazole-containing Derivatives of Sorafenib as Antitumor Agents

A series of hydrazine and oxadiazole analogs of Sorafenib was designed, synthesized and characterized by proton nuclear magnetic resonance（1H NMR） spectrometry and high resolution mass spectrometry（HRMS）. The anti-proliferative activities of these compounds against human colorectal earcinoma（HCT-116） and human breast cancer （MDA-MB-231） tumor cell lines were evaluated in vitro by MTT method[MTT=3-（4,5-dimethylthiazol-2-yl）-2,5- diphenyltetrazolium bromide]. The bioassay results suggest that most of the synthesized compounds have antitumor potential to HCT-116 cell line compared with MDA-MB-231 cell line. Compounds 8a, 8b, 8d, Be, 9f and 9j competitive with Sorafenib demonstrated antiproliferative activities on HCT-116 cell line.

ANTITUMOR PRINCIPLES OF STELLERA CHAMAEJASME L.

Methanol extract of Stellera chamaejasme L wasassessed for antitumor activity by an antitumor activebioassay against murine leukemia P388 in vivo. Thebioassay-directed separation of the extract furnishedseven diterpene compounds (stellerarin, stelleramacrin,gnidimacrin, pimelea factor P2, subtoxin, huratoxin,simplexin ) and two biflavanone compounds (neochemae-jasmin A and B). Among them, gnidimacrin, stellerarinand stelleramacrin (a novel compound) were found tohave high antitumor and cytotoxic activities against P388,L1210 and K562 in vivo and in vitro. The results suggestedthat the diterpene compounds were the potent anti-tumor principles of Stellera chamaejame L

Actinolactomycin,a New 2-Oxonanonoidal Antitumor Antibiotic Produced by Streptomyces flavoretus 18522,and its Inhibitory Effect on the Proliferation of Human Cancer Cells

Actinolactomycin 1, a new 2-oxonanonoidal antitumor antibiotic, was isolated from the fermentation broth of Streptomyces flavoretus 18522 through a bioassay-guided separation procedure. The structure of 1 was determined as 4,7-dihydroxy-3,9-dimethyl-2-oxonanone by the spectroscopic methods. Compound 1 inhibited the proliferation of A2780, K562, HCT-15, A549 and HeLa cells with the IC50 values of 1.4 ± 0.4 μmol/L, 8.4 ± 4.7 μmol/L, 9.4 ± 2.2 μmol/L, 15.4 ± 5.6 μmol/L and 13.7 ± 2.0 μmol/L, respectively. Flow cytometric analysis indicated that 1 could inhibit the cell cycle of tsFT210, A2780 and K562 cells mainly at the G0/G1 phase and could also induce apoptosis in K562 cells.

Novel insights into conjugation of antitumor-active unsymmetrical bisacridine C-2028 with glutathione:Characteristics of non-enzymatic and glutathione S-transferase-mediated reactions

Unsymmetrical bisacridines(UAs) are a novel potent class of antitumor-active therapeutics.A significant route of phase II drug metabolism is conjugation with glutathione(GSH),which can be non-enzymatic and/or catalyzed by GSH-dependent enzymes.The aim of this work was to investigate the GSHmediated metabolic pathway of a representative UA,C-2028.GSH-supplemented incubations of C-2028 with rat,but not with human,liver cytosol led to the formation of a single GSH-related metabolite.Interestingly,it was also revealed with rat liver microsomes.Its formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450(CYP450) inhibitor 1-aminobenzotriazole.Therefore,the direct conjugation pathway occurred without the prior CYP450-catalyzed bioactivation of the substrate.In turn,incubations of C-2028 and GSH with human recombinant glutathione S-transferase(GST) P1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form,respectively.These findings proved the necessary participation of GST in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate molecule.Another C-2028-GSH S-conjugate was also formed during non-enzymatic reaction.Both GSH S-conjugates were characterized by combined liquid chromatography/tandem mass spectrometry.Mechanisms for their formation were proposed.The ability of C-2028 to GST-mediated and/or direct GSH conjugation is suspected to be clinically important.This may affect the patient’s drug clearance due to GST activity,loss of GSH,or the interactions with GSH-conjugated drugs.Moreover,GST-mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.

Preparation of Platinum(II) Complexes with 1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide and its Deoxy-analogue

The platinum (II) complexes of the [Pt (N4,N7-Ribavirin) (DMSO) Cl], [Pt (N4,N7-De-oxyribavirin) (DMSO) Cl] were obtained by the reactions of cis-[Pt (DMSO)2 Cl2] and K[Pt (DMSO) Cl3] with 1-??-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Ribavirin) and its deoxy-analogue (deoxyribavirin). The preparation of 1-(2'-deoxy-?-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide was also performed through a four-step procedure, protection of 3', 5'-dihydroxyl group of Ribavirin with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TPDS-Cl), phenoxythio-carbonylation of the 2'-hydroxyl group of 3', 5'-O-TPDS-Ribavirin with phenoxythiocarbonyl-chloride (PTC-Cl), reduction of 2′-O-phenoxythiocarbonyl ester of 3', 5'-O-TPDS-Ribavirin with tri-n-butyltin hydride and AIBN, deprotection of 3', 5'-O-TPDS-Ribavirin with tetrabutylammon-ium fluoride in THF.

A Novel Vascular Disrupting Agents Noncovalent Polymeric Nanomedicine:Significantly Increased Antitumor Therapeutic Efficiency

This work was supported by the National Natural Science Foundation of China(Nos.52025035,52103195).The comprehensive graphic content and graphic abstract were created with BioRender.com by coauthors.

Crystal Structure of O，O－Diethyl－α－（β－triphenylgermanyl）－propionoyloxy Methylphosphonate

C26H31GeO5P is monoclinic,space group P21/c,a=14.287（4）,b=8.045（2）,c=23.381（6）,β=103.79（2）°,V=2622.7,Mr=527.10,Z=4,Dx=1.34g/cm3,μ=12.4cm.F（000）=1096.The final R=0.051 and Rw=0.057 for 2446 observed unique reflections[I≥3σ（I）.The results indicated that all non-hydrogen atoms between phosphorus and germanium in the title compound were located almost in coplane with farthest deviation of atom Ge defined by 0. 3657.The values of Ge-C（phenyl） and Ge-C（alkyl） bond distance are 1.938（5）,1.945（5） and 1.976（5）,respectively.

Design,synthesis,and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors

MicroRNA-21(miRNA-21)is highly expressed in various tumors.Small-molecule inhibition of miRNA-21 is considered to be an attractive novel cancer therapeutic strategy.In this study,fluoroquinolone derivatives A1eA43 were synthesized and used as miRNA-21 inhibitors.Compound A36 showed the most potent inhibitory activity and specificity for miRNA-21 in a dual-luciferase reporter assay in HeLa cells.Compound A36 significantly reduced the expression of mature miRNA-21 and increased the protein expression of miRNA-21 target genes,including programmed cell death protein 4(PDCD4)and phosphatase and tensin homology deleted on chromosome ten(PTEN),at 10 μM in HeLa cells.The Cell Counting Kit-8 assay(CCK-8)was used to evaluate the antiproliferative activity of A36;the results showed that the IC_(50) value range of A36 against six tumor cell lines was between 1.76 and 13.0 μM.Meanwhile,A36 did not display cytotoxicity in BEAS-2B cells(lung epithelial cells from a healthy human donor).Furthermore,A36 significantly induced apoptosis,arrested cells at the G_(0)/G_(1) phase,and inhibited cell-colony formation in HeLa cells.In addition,mRNA deep sequencing showed that treatment with A36 could generate 171 dysregulated mRNAs in HeLa cells,while the expression of miRNA-21 target gene dual-specificity phosphatase 5(DUSP5)was significantly upregulated at both the mRNA and protein levels.Collectively,these findings demonstrated that A36 is a novel miRNA-21 inhibitor.

Syntheses of 2- or 6-Substituted Chromones and Chromone Ring-opening Reaction in Polyphosphoric Acid

In an attempt to find new antitumor agents,a novel class of chromone compounds with a benzimidazole or a benzoxazole ring in positions 2 or 6 were synthesized via condensation in polyphosphoric acid(PPA) by using chromone acids as the starting materials. During the preparation process,it was found that PPA could cleave the chromone ring to produce a ring-opening compound(6). The molar ratio of the chromone compound(5) to the ring-opening compound(6) varied with the change of reaction temperature and time. Based on MTT protocol,the antitumor activity of each of the compounds obtained was evaluated against three human cancer cell lines: KB(oral epidermal),A2780(ovary) and Bel7402(liver). The IC_ 50 varied from 54.7 μmol/L to more than 180 μmol/L.

Glycoconjugation: An approach to cancer therapeutics

Cancer constitutes the second leading cause of death globally and is considered to have been responsible for an estimated 9.6 million fatalities in 2018.Although treatments against gastrointestinal tumors have recently advanced,those interventions can only be applied to a minority of patients at the time of diagnosis.Therefore,new therapeutic options are necessary for advanced stages of the disease.Glycosylation of antitumor agents,has been found to improve pharmacokinetic parameters,reduce side effects,and expand drug half-life in comparison with the parent compounds.In addition,glycosylation of therapeutic agents has been proven to be an effective strategy for their targeting tumor tissue,thereby reducing the doses of the glycodrugs administered to patients.This review focusses on the effect of the targeting properties of glycosylated antitumor agents on gastrointestinal tumors.

Photothermally Enhanced Dual Enzyme-mimic Activity of Gold-Palladium Hybrid Nanozyme for Cancer Therapy

Based on characteristics of the tumor microenvironment(TME),including acidity,hypoxia,inflammation and hydrogen peroxide overload,combined with emerging nanotechnologies,designing nanoplatforms with TME specificity/responsiveness for tumor treatment is a promising nanotherapeutic strategy.In this work,a multifunctional gold-palladium bimetallic cascade nanozyme was constructed for effective photothermal-enhanced cascade catalyzed synergistic therapy of tumors.The dumbbell-like Au-Pd bimetallic nanomaterial(Au NRs-Pd@HA)was obtained by reducing palladium on gold nanorods with ascorbic acid(AA)and further modified with hyaluronic acid(HA).The introduction of HA brings biocompatibility and targeting properties.The zebrafish embryos model showed that Au NRs-Pd@HA had good biocompatibility and low biotoxicity.Au NRs-Pd@HA can induce catalytic conversion of glucose to generate H_(2)O_(2) efficiently,and subsequently undergo cascade reaction to produce abundant·OH radicals,exhibiting peroxidase-like(POD-like)and glucose oxidase-like(GOD-like)capabilities.The generated·OH was a key factor for tumor ablation.Meanwhile,Au NRs-Pd@HA exhibits good photothermal performance under 808 nm irradiation,in favor of photothermal therapy(PTT).Especially,the POD-like and GOD-like activities were significantly enhanced due to the photothermal effect.The synergistic PTT and photothermal-enhanced nanozymes with cascade catalytic effect enabled efficient and safe cancer therapy.

In silico design of anti-tumor mini-protein targeting MDM2

We designed a disulfide-crosslinked mini-protein with a two-helical topology consisting of L-and Damino acids,which was exceptionally stable in serum.Therefore,we further used it as a scaffold to design mini-proteins targeting p53 positive tumor cells.Based on bifunctional grafting,key residues from the transactivation domain of p53 and a designed unnatural amino acid were grafted into the helix constituted by L-amino acids to confer the mini-protein with MDM2 inhibitory activity.Meanwhile,ten Arg residues were introduced to improve its membrane penetrating capacity.Among the mini-proteins,UPROL-10e showed nano-molar binding affinity on MDM2 and cellular toxicity on p53 expressing HCT116cells.

5-Fluorouracil derivatives ⅩⅩⅢ. Synthesis and antitumor activities of 1-carbamoyl-5-fluorouracils having aromatic ring

In order to get good antitumor agents especially better than 5-fluorouracil,tegafur and l-hexylcarbamoyl-5-fluorouracil (HCFU),fourty nine 1-carbamoyl-5-fluorouracil having aromatic ring were synthesized from 5-fluorouracil and isocyanates or amines.Antitumor activity was tested in the L-1210 tumor system,and 5 compounds gave better value of therapeutic ratio than 5-fluorouracil,tegafur,HCFU.l-(4-Methoxybenzylcarbamoyl)-5-fluorouracil gave the best result.

Epigallocatechin-3-gallate Modulates MicroRNA Expression Profiles in Human Nasopharyngeal Carcinoma CNE2 Cells

Background： Epigallocatechin-3-gallate （EGCG） has exhibited antitumor properties in several types of cancers, including nasopharyngeal carcinoma （NPC）, but the molecular mechanisms underlying this function remain incompletely understood. The aim of the present study was to characterize the global impact of EGCG on the expression of microRNAs （miRNAs） in NPC cells. Methods： Using microarray analysis, the alterations of miRNA expression profiles were investigated in EGCG-treated CNE2 cells. Furthermore, the target genes and signaling pathways regulated by EGCG-specific miRNAs were identified using target prediction program and gene ontology analysis. Results： A total of 14 miRNAs exhibited 〉2-fold expression changes in a dose-dependent manner after treatment with 20 μmol/L and 40 μmol/L EGCG. Totally 43, 49, and 52 target genes from these differentially expressed miRNAs were associated with the apoptosis, cell cycle regulation, and cell proliferation, respectively. A total of 66 signaling pathways, primarily involved in cancer development and lipid and glucose metabolism, were shown to be regulated by EGCG-specific miRNAs. Conclusion： EGCG induces considerable alterations of miRNA expression profiles in CNE2 cells, which provides mechanistic insights into cellular responses and antitumor activity mediated by EGCG.

Precise Control of Self-assembly in vivo Based on Polymer-Peptide Conjugates

The self-assembled nanomaterials based on peptides,which have not only good biocompatibility and low toxicity but also high stability and performance,are increasingly becoming an important way for cancer treatment.In this review,we highlight the progress of in vivo self-assembled polymer-peptide conjugates(PPCs)and their application,showing the recent advances in the development of“in vivo self-assembly”strategy for cancer treatment.Given the diverse microenvironments of tumor cells,different responsive assembly strategies(enzyme,pH,redox,temperature,etc.)have been developed to precisely control the assembly at different biological levels,realizing enhanced drug delivery and improved anticancer efficacy.

Lithocarpins E-G, Potent Anti-Tumor Tenellone-Macrolides from the Deep-Sea Fungus Phomopsis lithocarpus FS508

Lithocarpins E-G,featuring a rare naturally-occurring highly oxygenated tenellone-macrolide skeleton,were isolated from the culture extract of a marine-derived fungus Phomopsis lithocarpus FS508.Their structures were fully elucidated by NMR and MS spectroscopic analyses and electronic circular dichroism calculations.Compounds 1-3 were evaluated for their in vitro cytotoxicities against HepG2,MCF-7,SF-268,as well as A549 cell lines,among which,compound 1 exhibited inhibitory activity against HepG2 cells with an IC_(50) value of 6.3 μmol/L.The further mechanistic investigation demonstrated that lithocarpin E could cause the apoptosis of HepG2 cells through activation of p-ERK,Bax,and caspase-3 gene expressions.

Erlotinib Analogue-substituted Zinc（Ⅱ） Phthalocyanines for Small Molecular Target-based Photodynamic Cancer Therapy

＂Smart＂ targeted photosensitizer conjugated with small molecule target-based anticancer drug which has a sim- ple chemical structure and high stability, is a new promising targeted therapeutic strategy. We herein extended this strategy and reported a novel series of zinc（II） phthalocyanine-erlotinib analogue conjugates with different periph- eral substituted positions and lengths of the linker. Having erlotinib analogue as the targeting moiety, all conjugates exhibited high specificity and potent affinity to HepG2 cancer cells and kept high photodynamic activity （ICs0 = 3.7 -- 16.7 nmol/L）. Structure-activity relationships of these conjugates were assessed by investigating their photophys- ical/photochemical properties, targeting intracellular uptake and in vitro phototoxicity. The results suggested that a-substituted conjugates showed slightly higher photodynamic activity than ,8-substituted ones. In conclusion, we have developed a series of promising anticancer agents with high tumor selectivity and anticancer activity for targeted photodynamic therapy.