Novel DNA-directed alkylating agents: Design,synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker

A series of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker was synthesized for antitumor evaluation. The carbamate or carbonate linker is able to lower the reactivity of the phenyl N-mustard pharmacophore and thus, these conjugates are rather chemically stable. The in vitro studies revealed that these derivatives possessed significant cytotoxicity with IC₅₀ in sub-micromolar range in inhibiting human lymphoblastic leukemia (CCRF-CEM), breast carcinoma (MX-1), colon carcinoma (HCT-116) and human non-small cell lung cancer (H1299) cell growth in vitro. Compounds 10a, 10b, 10e, 10i, and 15a were selected for evaluating their antitumor activity in nude mice bearing MX-1 and HCT-116 xenografts. Remarkably, total tumor remission was achieved by these agents with only one cycle of treatment. Interestingly, no tumor relapse was found in mice treated with 10a over 129 days. This agent is capable of inducing DNA interstrand cross-linking in human non-small lung cancer H1299 cells in a dose dependent manner by modified comet assay and has a long half-life in rat plasma.     

Design and synthesis of a new generation of substituted purine hydroxamate analogs as histone deacetylase inhibitors

Histone deacetylase inhibitors have been proved to be great potential for the treatment of cancer. Recently, we designed and modified a series of substituted purine hydroxamate analogs as potent HDAC inhibitors based on our previous studies. The target compounds were investigated for their in vitro HDAC inhibitory activities and anti-proliferative activities. Results indicated that these compounds could effectively inhibit HDAC and possess obvious anti-proliferative activity against tumor cells. Promisingly, target compounds 4m and 4n outperformed SAHA in both enzymatic inhibitory activity and cellular anti-proliferative activity assay.     

A novel metformin derivative,HL010183, inhibits proliferation and invasion of triple-negative breast cancer cells

Mounting evidence suggests that metformin (N,N-dimethylbiguanide), a widely prescribed drug for the treatment of type II diabetes, exerts an anti-tumor effect on several cancers including breast cancer. Breast cancer has been estimated as one of the most commonly diagnosed types of cancer among women. In particular, triple-negative breast cancers are associated with poor prognosis and metastatic growth. In the present study, we synthesized a novel metformin derivative 5 (HL010183) and metformin salts, 9a, 9b, and 9c (metformin gamma-aminobutyric acid (GABA) salt, metformin pregabalin salt and metformin gabapentin salt), which exerted more potent inhibitory effects on the proliferation and invasiveness of Hs578T triple-negative breast carcinoma cells than metformin. Importantly, 5 showed approximately 100-fold more potent effects compared to metformin. In a triple-negative breast cancer xenograft model, 5 showed a comparable degree of inhibitory effect on in vivo tumor growth at the 100 mg/kg dose to that of metformin at 500 mg/kg. Our results clearly demonstrate that 5 exerts a potent anti-tumor effect both in vitro and in vivo, paving the way for a strategy for treatment of triple-negative breast cancer.     

New antitumoral agents I: In vitro anticancer activity and in vivo acute toxicity of synthetic 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one and derivatives

This paper describes a new method for the preparation of 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one 1 and its derivatives 2–5. This set of synthetic compounds exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines as lung carcinoma NCI-460, melanoma UACC-62, breast MCF-7, colon HT-29, renal 786-O, ovarian OVCAR-03 and ovarian expressing the resistance phenotype for adriamycin NCI-ADR/RES, prostate PC-3, and leukemia K-562. Compounds were also tested against murine tumor cell line B16F10 melanoma and lymphocytic leukemia L1210 as well as to their effect toward normal macrophages. Specific activity against colon cancer cells HT-29 was observed for all tested compounds and suggests further studies with models of colon cancer. Compounds 1, 2, and 4 showed significant cytotoxic activity with IC₅₀ values ?2.3 μM for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate.     

Synthesis and anticancer activities of novel 3,5-disubstituted-1,2,4-oxadiazoles

A series of 3,5-disubstituted-1,2,4-oxadiazoles were synthesized and evaluated for their in vitro anti-proliferative activities against various cancer cell lines. Formation of 1,2,4-oxadiazole ring was accomplished by the reaction of amidoxime with carboxylic acids. The in vitro cytotoxic effects of 3,5-disubstituted-1,2,4-oxadiazoles have been demonstrated across a wide array of tumor cell types and a few compounds exhibited specificity towards pancreatic (3f, 3h, 3j, and 3k) and prostate (3n) cancer cells. Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 3n is the most selective (>450-fold) and compound 3p is the most cytotoxic (10 nM) against prostate cancer cell lines.     

Degrasyn-like symmetrical compounds: Possible therapeutic agents for multiple myeloma (MM-I)

A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.     

Synthesis and biological evaluation of paclitaxel and vorinostat co-prodrugs for overcoming drug resistance in cancer therapy in vitro

Paclitaxel (PTX) is the first-line treatment drug for breast cancer. However, drug resistance after a course of treatment and low selectivity restricted its clinical utility sometimes. In this study, we successfully bound PTX and vorinostat (SAHA) to form co-prodrugs based on the synergistic anticancer effects. The PTX-SAHA co-prodrugs were conjugated by glycine (1a) and succinic acid (1b) respectively and the former has shown better activity in cytotoxicity, cell cycle arrest and western-blot experiments. Therefore, 1a was further prepared to nanomicelles with mPEG₂₀₀₀-PLA₁₇₅₀ as the carrier by using thin film method. PTX-SAHA co-prodrug nanomicelles were spherical with a particle size of 20–100?nm. In vitro drug release test showed 1a nanomicelles had sustained release effect, which could reduce the resistance of PTX. In vitro cytotoxicity was evaluated by SRB assay in HCT-116 cells, MCF-7 cells and drug-resistant MCF-7/ADR cells. The results showed 1a nanomicelles had comparable or even better cytotoxicity than PTX especially in the MCF-7/ADR cells. All the results suggested that PTX-SAHA co-prodrug nanomicelles were promising treatment for PTX resistance cancer.     

Circulating Tumor DNA as Biomarkers for Cancer Detection

Detection of circulating tumor DNAs (ctDNAs) in cancer patients is an important component of cancer precision medicine ctDNAs. Compared to the traditional physical and biochemical methods, blood-based ctDNA detection offers a non-invasive and easily accessible way for cancer diagnosis, prognostic determination, and guidance for treatment. While studies on this topic are currently underway, clinical translation of ctDNA detection in various types of cancers has been attracting much attention, due to the great potential of ctDNA as blood-based biomarkers for early diagnosis and treatment of cancers. ctDNAs are detected and tracked primarily based on tumor-related genetic and epigenetic alterations. In this article, we reviewed the available studies on ctDNA detection and described the representative methods. We also discussed the current understanding of ctDNAs in cancer patients and their availability as potential biomarkers for clinical purposes. Considering the progress made and challenges involved in accurate detection of specific cell-free nucleic acids, ctDNAs hold promise to serve as biomarkers for cancer patients, and further validation is needed prior to their broad clinical use.     

Anti-angiogenic and anticancer effects of baicalein derivatives based on transgenic zebrafish model

Angiogenesis leads to tumor neovascularization by promoting tumor growth and metastatic spread, therefore, angiogenesis is considered as an attractive target for potential small molecule anticancer drug discovery. Herein, we report the structural modification and biological evaluation of baicalein derivatives, among which compound 42 had potent in vivo anti-angiogenic activity and wide security treatment window in transgenic zebrafish model. Further, 42 exhibited the most potent inhibitory activity on HUVEC proliferation, migration and tube formation in vitro. Moreover, 42 significantly inhibited growth of human lung cancer A549 cells and weak influence on human normal fibroblast L929 cells. The present research demonstrated that the significant anti-angiogenic and anticancer effects, which provided the supportive evidence for 42 could be used as a potential compound of cancer therapy.     

Synthesis and biological evaluation of NQO1-activated prodrugs of podophyllotoxin as antitumor agents

Podophyllotoxin (PPT), a toxic polyphenol derived from the roots of genus Podophyllum, had been reported with strong inhibition on both normal human cells and tumor cells, which hindered the development of PPT as the candidate antitumor agent. In the present work, multiple NQO1-activatable PPT prodrugs were synthesized for reducing normal cell toxicity and keeping tumor cell toxicity. The antiproliferative activities in vitro showed prodrug 3 was greatly selectively toxic to tumor cells over-expressing NQO1, taxol-resistant A549, hypoxia A549 and HepG2, and lower damage to normal cells in comparison with podophyllotoxin, prodrug 1 and 2. As elucidated by further mechanistic research, prodrug 3 was activated via NQO1 to efficiently while gently produce cytotoxic PPT units and kill tumor cells. In additions, in vivo study revealed that 3 significantly suppressed cancer growth in HepG2 xenograft models without obvious toxicity. Therefore, this NQO1-activatable prodrug delivery system exhibits good biosafety and provides a novel strategy for the development of drug delivery systems.     

Synthesis,single crystal and antitumor activities of benzimidazole–quinazoline hybrids

A series of novel regioisomeric hybrids of quinazoline/benzimidazole viz. (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine and (1-allyl-2-methyl-1H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine of biological interest were synthesized. All the synthesized compounds were well characterized by ¹H and ¹³C NMR as well as mass spectroscopy. The newly synthesized compounds were screened for in vitro antitumor activities against 60 tumor cell lines panel assay. A significant inhibition for cancer cells were observed with compound 9 and also more active against known drug 5-fluorouracil (5-FU) in some tumor cell lines. Compound 9 displayed appreciable anticancer activity against leukemia, colon, melanoma, renal and breast cancer cell lines.     

Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells

Under hypoxia, cancer cells consume glucose and release lactate at a high rate. Lactate was recently documented to be recaptured by oxygenated cancer cells to fuel the TCA cycle and thereby to support tumor growth. Monocarboxylate transporters (MCT) are the main lactate carriers and therefore represent potential therapeutic targets to limit cancer progression. In this study, we have developed and implemented a stepwise in vitro screening procedure on human cancer cells to identify new potent MCT inhibitors. Various 7-substituted carboxycoumarins and quinolinone derivatives were synthesized and pharmacologically evaluated. Most active compounds were obtained using a palladium-catalyzed Buchwald–Hartwig type coupling reaction, which proved to be a quick and efficient method to obtain aminocarboxycoumarin derivatives. Inhibition of lactate flux revealed that the most active compound 19 (IC₅₀ 11 nM) was three log orders more active than the CHC reference compound. Comparison with warfarin, a conventional anticoagulant coumarin, further showed that compound 19 did not influence the prothrombin time which, together with a good in vitro ADME profile, supports the potential of this new family of compounds to act as anticancer drugs through inhibition of lactate flux.     

Synthesis of new conjugated coumarin–benzimidazole hybrids and their anticancer activity

A series of novel coumarin–benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A significant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition) compared with other compounds and active known drug 5-fluorouracil (in some cell lines) as positive control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and breast cancer cell lines.     

Selective accumulation of [62Zn]-labeled glycoconjugated porphyrins as multi-functional positron emission tomography tracers in cancer cells

Positron-emission tomography (PET) can be used to visualize active stage cancer. Fluorine-18 ([¹⁸F])-labeled 2-([¹⁸F])2-deoxy-2-fluoroglucose (([¹⁸F])-FDG), which accumulates in glucose-dependent tissues, is a good cancer-targeting tracer. However, ([¹⁸F])-FDG is obscured in glucose-dependent normal tissues. In this study, we assessed the cancer-selective accumulation of zinc-labeled glycoconjugated 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (ZnGlc1–4), both in vitro and in vivo. Experiments using both normal and cancer cells confirmed the relationship between cancer cell-selective accumulation and the substitution numbers and orientations of glycoconjugated porphyrins. ZnGlctrans-2 accumulated at greater levels in cancer cells compared with other glycoconjugated porphyrins. PET imaging showed that ZnGlctrans-2 accumulated in tumor.     

Pyrazolobenzodiazepines: Part I. Synthesis and SAR of a potent class of kinase inhibitors

A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure–activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents.     

A benzenesulfonamide derivative as a novel PET radioligand for CXCR4

CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC₅₀ = 6.9 nM) against a known CXCR4 antagonist (TN14003) and inhibits more than 65% chemotaxis at 10 nM in vitro assays. Radiofluorinated compound 5 ([¹⁸F]5) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [¹⁸F]5 exhibits preferential accumulation of radioactivity in the lesions of λ-carrageenan-induced paw edema, human head and neck cancer orthotopic xenograft, and metastatic lung cancer of each mouse model.     

eTumorType,An Algorithm of Discriminating Cancer Types for Circulating Tumor Cells or Cell-free DNAs in Blood

With the technology development on detecting circulating tumor cells(CTCs) and cellfree DNAs(cf DNAs) in blood, serum, and plasma, non-invasive diagnosis of cancer becomes promising. A few studies reported good correlations between signals from tumor tissues and CTCs or cf DNAs, making it possible to detect cancers using CTCs and cf DNAs. However, the detection cannot tell which cancer types the person has. To meet these challenges, we developed an algorithm,e Tumor Type, to identify cancer types based on copy number variations(CNVs) of the cancer founding clone. e Tumor Type integrates cancer hallmark concepts and a few computational techniques such as stochastic gradient boosting, voting, centroid, and leading patterns. e Tumor Type has been trained and validated on a large dataset including 18 common cancer types and 5327 tumor samples. e Tumor Type produced high accuracies(0.86–0.96) and high recall rates(0.79–0.92) for predicting colon, brain, prostate, and kidney cancers. In addition, relatively high accuracies(0.78–0.92)and recall rates(0.58–0.95) have also been achieved for predicting ovarian, breast luminal, lung, endometrial, stomach, head and neck, leukemia, and skin cancers. These results suggest that e Tumor Type could be used for non-invasive diagnosis to determine cancer types based on CNVs of CTCs and cf DNAs.     

Carbonic anhydrase inhibitors: Synthesis,molecular docking,cytotoxic and inhibition of the human carbonic anhydrase isoforms I,II, IX,XII with novel benzenesulfonamides incorporating pyrrole,pyrrolopyrimidine and fused pyrrolopyrimidine moieties

A series of novel pyrroles, pyrrolopyrimidines, pyrazolopyrrolopyrimidine, triazolopyrrolopyrimidines, tetrazolopyrrolopyrimidine, triazinopyrrolopyrimidines and pyrrolopyrimidotriazepines bearing the biologically active benzenesulfonamide moiety were synthesized by using pyrrole-o-amino-carbonitrile as key intermediate. All the synthesized compounds were evaluated for their in vitro carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects against the human (h) isoforms hCA I, II, IX and XII. Among the tested derivatives, compounds 16, 18 and 20–24 showed potent activity as inhibitors for the tumor associated transmembrane isoforms (hCA IX and XII) in the nanomolar and subnanomolar range, with high selectivity. All compounds underwent cytotoxic activity assays on human breast cancer cell line (MCF-7) showing effective activity, comparable to that of the clinically used drug doxorubicin.     

Novel inhibitors of human glucose-6-phosphate dehydrogenase (HsG6PD) affect the activity and stability of the protein

BackgroundThe pentose phosphate pathway (PPP) has received significant attention because of the role of NADPH and R-5-P in the maintenance of cancer cells, which are necessary for the synthesis of fatty acids and contribute to uncontrollable proliferation. The HsG6PD enzyme is the rate-limiting step in the oxidative branch of the PPP, leading to an increase in the expression levels in tumor cells; therefore, the protein has been proposed as a target for the development of new molecules for use in cancer.MethodsThrough in vitro studies, we assayed the effects of 55 chemical compounds against recombinant HsG6PD. Here, we present the kinetic characterization of four new HsG6PD inhibitors as well as their functional and structural effects on the protein. Furthermore, molecular docking was performed to determine the interaction of the best hits with HsG6PD.ResultsFour compounds, JMM-2, CCM-4, CNZ-3, and CNZ-7, were capable of reducing HsG6PD activity and showed noncompetitive and uncompetitive inhibition. Moreover, experiments using circular dichroism and fluorescence spectroscopy showed that the molecules affect the structure (secondary and tertiary) of the protein as well as its thermal stability. Computational docking analysis revealed that the interaction of the compounds with the protein does not occur at the active site.ConclusionsWe identified two new compounds (CNZ-3 and JMM-2) capable of inhibiting HsG6PD that, compared to other previously known HsG6PD inhibitors, showed different mechanisms of inhibition.General significanceScreening of new inhibitors for HsG6PD with a future pharmacological approach for the study and treatment of cancer.     

Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity

There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefitinib. The anti-tumor activity of these novel Gefitinib analogues in 6 human cancer cell lines was examined. Compared with the parental Gefitinib, most of the new compounds show a markedly increased cytotoxicity to cancer cells. Furthermore, several of the series B compounds that side chains at position 7 contain either a methyl or ethyl group are potent pan-RTK inhibitors. Two representative compounds in this class, 15 and 17, have an enhanced capability to inhibit cancer cell growth and induce apoptosis in vitro and inhibit tumor formation in vivo in human cancer cells with high HER-2, as compared with the parental Gefitinib. Thus they may be promising lead compounds to be developed as an alternative for current Gefitinib therapy or for Gefitinb-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.