Potent Antiproliferative Agents Research Articles

Synthesis of MeON-Glycoside Derivatives of Oleanolic Acid by Neoglycosylation and Evaluation of Their Cytotoxicity Against Selected Cancer Cell Lines.

A series of C-3 and C-28 MeON-neoglycosides of oleanolic acid were designed and synthesized by neoglycosylation as potential antiproliferative agents. Their cytotoxicity was evaluated in vitro against five human cancer cell lines: human non-small cell lung cancer cell line (A549), human melanoma cell line (A375), human colon cancer cell line (HCT116), human liver carcinoma cell line (HepG2), human breast adenocarcinoma cell line (MCF-7) by the Cell Counting Kit-8 (CCK-8) assay. Most of C-3 and C-28 MeON-neoglycosides of oleanolic acid exhibited notably inhibitory effects against the tested cancer cells and more sensitive to HepG2 cells than 5-Fluorouracil (5-FU). Structure-activities relationship (SAR) analysis revealed that sugar types and the d/l configuration of sugars would significantly affect their antiproliferative activities of neoglycosides. Among them, compound 8a (28-N-methoxyaminooleanane-β-d-glucoside) exhibited the most potent antiproliferative activities against HepG2 cells with IC50 values of 2.1 µM. Further pharmacological experiments revealed that compound 8a could cause morphological changes and cell cycle arrest at G0/G1 phase and induce apoptosis in HepG2 cells. These results suggested that neoglycosylation could provide a rapid strategy for the discovery of potential antiproliferative agents and their possible pharmacological mechanisms need more further research.

Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer

In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a–e and 7a–i) was designed and synthesised. The anticancer activity for compounds (5b–d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a–e and 7a–i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC50 = 8.7 and 9.4 µM (5a), and 6.5 and 9.8 µM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.

Chromium (III) Complexes of 4,5-diazafluoren-9-one Ligand as Potential Anti-proliferative Agents: Synthesis, Characterization, DNA Binding, Molecular Docking and In-vitro Cytotoxicity Evaluation.

Three novel Cr(III) complexes, [Cr(dafone)2(H2O)2](NO3)3 (1), [Cr(opd) (dafone)2](NO3)3 (2) and [Cr (phen-dione) (dafone) (H2O)2].(NO3)3 (3) were synthesized and characterized by different techniques. Fluorescence spectroscopy, gel electrophoresis, viscosity measurement, and circular dichroism (CD) were applied to explore the interaction of Cr complexes with FS-DNA. The binding constant (Kb) was obtained from UV–Vis measurements. The obtained results exhibited the effective binding of target complexes to DNA double-strand. The fluorescence data appraised both binding and thermodynamic constants of complexes-DNA interactions. The measured thermodynamic factors (∆S˚, ∆H˚, ∆G˚) revealed that hydrogen bonding and van der Waals forces for DNA- Cr(III) complexes bear the most important roles. As well, the Stern–Volmer quenching constants (Ksv) and the binding constants (Kb) of synthesized compounds and DNA were calculated. The results of thermodynamic parameters showed that the binding of synthesized Cr(III) compounds to DNA was driven mainly through hydrogen bonds and van der Waals interactions. Viscosity measurement results showed that increasing the concentration of synthesized compounds, did not make any major changes in specific viscosity of FS-DNA. The data of viscosity and circular dichroism (CD) support the groove binding mode.

Evaluation of imidazo[2,1–b]thiazole-based anticancer agents in one decade (2011–2020): Current status and future prospects

Several reports have highlighted imidazo[2,1-b]thiazole derivatives as potential antiproliferative agents. They act through kinase inhibition, tubulin inhibition, and other molecular mechanisms of action. In the current article, we reviewed the imidazo[2,1-b]thiazole-based compounds that were reported as anticancer agents. Their biological characteristics as well as structure–activity relationship (SAR) have been reviewed and evaluated. Our main focus was on the reports published in the literature from 2011 to 2020.

Design and synthesis of novel quinoline/chalcone/1,2,4-triazole hybrids as potent antiproliferative agent targeting EGFR and BRAFV600E kinases

New quinoline / chalcone hybrids containing 1,2,4-triazole moiety have been designed, synthesized and their structures elucidated and confirmed by various spectroscopic techniques. The designed compounds showed moderate to good activity on different NCI 60 cell lines in a single-dose assay with a growth inhibition rate ranging from 50% to 94%. Compounds 7b, 7d, 9b, and 9d were the most active compounds in most cancer cell lines with a growth inhibition percent between 77% and 94%. Newly synthesized hybrids were evaluated for their anti-proliferative activity against a panel of four human cancer cell lines. Compounds 7a, 7b, 9a, 9b, and 9d showed promising antiproliferative activities. These compounds were further tested for their inhibitory potency against EGFR and BRAFV600E kinases with erlotinib as a reference drug. The molecular docking study of compounds 7a, 7b, 9a, 9b, and 9d revealed nice fitting into the active site of EGFR and BRAFV600E kinases. Compounds 7b, 9b, and 9d displayed the highest binding affinities and similar binding pattern to those of erlotinib.

Antiproliferative activity exerted by tricyclohexylphosphanegold(I) n-mercaptobenzoate against MCF-7 and A2780 cell lines: the role of p53 signaling pathways.

Based on the recent studies depicting the potential of heterometallic gold complexes as potent antiproliferative agents, herein we first reported the preliminary mechanistic data on the in-vitro antiproliferative activity of tricyclohexylphosphanegold(I) n-mercaptobenzoate, Cy3PAu(n-MBA) where n = 2 (1), 3 (2) and 4 (3), and MBA = mercaptobenzoic acid, treated using MCF-7 breast cancer and A2780 ovarian cancer cells, respectively. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to assess the cytotoxicity of both cancer cells treated with 1-3, respectively. The IC50 of 1-3 were applied to the subsequent assays including cell invasion and thioredoxin reductase (TrxR) as well as ubiquitin activities specifically on Lys48 and Lys63-linked polyubiquitin chains via flowcytometric analysis. The mechanistic effect of 1-3 towards both cells were evaluated on human p53 signaling gene expressions via RT2 profiler Polymerase Chain Reductase (PCR) array. 1-3 were found to be highly cytotoxic towards both MCF-7 and A2780 cancer cell lines with the compounds were more sensitive towards the latter cells. 1-3 also suppressed TrxR and cell invasion activities by modulating p53 related genes related with proliferation, invasion and TrxR activities i.e. CCNB1, TP53, CDK4 etc. 1-3 also regulated Lys48 and Lys63-linked polyubiquitination by reactivation of p53, suggesting the ability of this gene in regulating inhibition of cytoskeletal reorganization via epithelial-mesenchymal transition (EMT), required for tumor progression. Taken together, the overall findings denoted that 1-3 exerted potent antiproliferative activity in MCF-7 and A2780 cells via activation of the p53 signaling pathway.

Potent antiproliferative active agents: novel bis Schiff bases and bis spiro β-lactams bearing isatin tethered with butylene and phenylene as spacer and DNA/BSA binding behavior as well as studying molecular docking

A [2+2]-cycloaddition of bis-isatin Schiff bases 5a–b and 7 with activated aryloxyacetic acid derivatives 8a–d afforded bis-spiroisatino β-lactams with aliphatic and aromatic spacers. The structures of the synthesized 2-oxindoles and spirooxindoles were determined based on Fourier-transform infrared spectroscopy, proton-1 and carbon-13 nuclear magnetic resonance spectroscopies and CHN analysis. Our interest in these bis-Schiff bases and bis-spiroisatino β-lactams is for their potential anticancer capabilities. In vitro bioactivity testing against the cervical adenocarcinoma (HeLa) and breast cancer (MCF-7) cell lines as well as noncancerous NIH/3T3 fibroblast cell was investigated applying the MTT assay. Bis-isatin derivatives 5a, 5b, 9h, 10a, and 10b showed promising antiproliferative activity toward these two cancer cell lines. Two of the bis-isatin Schiff bases, 5a and 5b, displayed IC50 values less than that of the clinically-used anticancer agent cisplatin towards both the MCF-7 and HeLa cells, while several of the bis-isatin β-lactams showed similar bioactivity to that of cisplatin. All of the oxindoles and spirooxindoles displayed a selective anticancer effect except 10b. To study the possible mechanism for this bioactivity, DNA and BSA binding analyses were performed using fluorescence and UV–visible spectroscopic techniques. The isatin adducts displayed excellent interaction propensity to CT-DNA as well as BSA. Molecular docking investigation carried out on DNA and BSA with promising molecules to show the possible mechanism of cytotoxicity activities.

Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice.

Simple SummaryRecently, the antiprogestin activity of selective progesterone receptor (PR) modulator mifepristone (MF) has proven unsuccessful as a potential anti-cancer agent in various clinical trials. Herein, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-α promoter-driven SV40 T-antigen), as well as on the proliferation of two Leydig tumor cell lines. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Only the abundant membrane Pgrmc1 expression was found in LCTs, but no other classical Pgr or nonclassical membrane PRs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Our findings provide novel information that the use of MF as an anti-cancer agent should be considered with caution due to its potential PGRMC1 tumor-promoting pathway activation in cancers.The selective progesterone receptor modulator mifepristone (MF) may act as a potent antiproliferative agent in different steroid-dependent cancers due to its strong antagonistic effect on the nuclear progesterone receptor (PGR). Hereby, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-α promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Traceable/absent classical Pgr or nonclassical membrane PRs α, β, γ and Pgrmc2, but abundant membrane Pgrmc1 expression, was found in LCTs. MF did not activate glucocorticoid or androgen receptors in LCTs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Accordingly, MF and P4 induced PGRMC1 translocation into the nucleus and thereby stimulated the release of TGFβ1 in LCT cells. MF and P4 treatments upregulated Tgfbr1, Tgfbr2, and Alk1 expression and stimulated TGFβ1 release in LCT cells. Our findings provide novel mechanistic insights into the action of MF as a membrane PR agonist that promotes LCT growth through PGRMC1 and the alternative TGFβ1 signaling pathway.

Synthesis and QSAR Studies of Novel Pyrazoline Derivatives as Antiproliferative Agent

Abstract: Background: Regardless of recent advances in the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. The revelation of the anticancer properties of pyrazoline makes this scaffold remarkable for research and development as an anticancer. Methods: A series of synthetic chalcones and pyrazoline derivatives were synthesized, characterized IR, 1H NMR and mass spectral analysis and evaluated for their Anticancer activity on MCF-7 cell line through SRB assay. A QSAR study was performed on thirtyfive compounds of known series having pyrazoline nucleus using Accelrys Discovery Studio Vs 2.1.0.8130. Results: We found that significant inhibitory activity among all the synthesized compound 1B showing better anticancer activity having IC50 value 0.010 μM as compared to standard drug letrozole. So predicted molecules from the QSAR study show significant activity. Conclusion: We would conclude that compound 1B might serve as a potential antiproliferative agent. Key words: Pyrazoline, QSAR, SRB assay, MCF-7, Antiproliferative activity.

Methylsulfanylpyridine based diheteroaryl isocombretastatin analogs as potent anti-proliferative agents.

Isocombretastatins are the not isomerizable 1,1-diarylethene isomers of combretastatins. Both families of antimitotics are poorly soluble and new analogs with improved water solubility are needed. The ubiquitous 3,4,5-trimethoxyphenyl ring and most of its replacements contribute to the solubility problem. 39 new compounds belonging to two series of isocombretastatin analogs with 2-chloro-6-methylsulfanyl-4-pyridinyl or 2,6-bis(methylsulfanyl)-4-pyridinyl moieties replacing the 3,4,5-trimethoxyphenyl have been synthesized and their antimitotic activity and aqueous solubility have been studied. We show here that 2-chloro-6-methylsulfanylpyridines are more successful replacements than 2,6-bis(methylsulfanyl)pyridines, giving highly potent tubulin inhibitors and cytotoxic compounds with improved water solubilities. The optimal combination is with indole rings carrying polar substitutions at the three position. The resulting diheteroaryl isocombretastatin analogs showed potent cytotoxic activity against human cancer cell lines caused by tubulin inhibition, as shown by invitro tubulin polymerization inhibitory assays, cell cycle analysis, and confocal microscopy studies. Cell cycle analysis also showed apoptotic responses following G2/M arrest after treatment. Conformational analysis and docking studies were applied to propose binding modes of the compounds at the colchicine site of tubulin and were in good agreement with the observed SAR. 2-Chloro-6-methylsulfanylpyridines represent a new and successful trimethoxyphenyl ring substitution for the development of improved colchicine site ligands.

Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as potent antiproliferative agents via a hybrid pharmacophore approach

Imiquimod (1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine) is efficacious in topical therapy for certain types of skin cancers. Structurally similar EAPB0203 (N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine) has been shown higher in vitro potency than imiquimod. Besides, triazole, oxadiazole, and thiadiazole rings are privileged building blocks in drug design. A series of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole and [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-thiadiazole derivatives were therefore synthesized by incorporation of these rings into the structure of EAPB0203 and assessed their antiproliferative effects against various cancer cell lines. The 1,3,4-oxadiazole derivatives demonstrated the superior effectiveness compared to imiquimod and EAPB0203. Our findings highlight the excellent potential of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as anticancer agents.

Pd-catalyzed Suzuki–Miyaura couplings and evaluation of 13α-estrone derivatives as potential anticancer agents

13α-Estrones are of great value owing to their potent multiple bioactivity, including anticancer activity. 3-OH or 3-OBn derivatives of 2- or 4-[(subst.) phenyl]-13α-estrone as potential antiproliferative agents have been synthesized via facile, microwave-induced, Pd-catalyzed Suzuki–Miyaura coupling. 2- or 4-Halogenated 13α-estrone derivatives have been reacted with (4-subst.)phenylboronic acids using Pd(PPh3)4 as catalyst. The nature of para substituents at the introduced phenyl group did not influence the outcome of couplings. Certain newly synthesized compounds displayed substantial antiproliferative action against human adherent cancer cell lines of gynecological origin. Important structure–activity relationships were revealed, which might be helpful in the design of potent and selective anticancer derivatives based on the hormonally inactive 13α-estrane core.

Ethiopian Medicinal Plants Traditionally Used for the Treatment of Cancer, Part 2: A Review on Cytotoxic, Antiproliferative, and Antitumor Phytochemicals, and Future Perspective.

This review provides an overview on the active phytochemical constituents of medicinal plants that are traditionally used to manage cancer in Ethiopia. A total of 119 articles published between 1968 and 2020 have been reviewed, using scientific search engines such as ScienceDirect, PubMed, and Google Scholar. Twenty-seven medicinal plant species that belong to eighteen families are documented along with their botanical sources, potential active constituents, and in vitro and in vivo activities against various cancer cells. The review is compiled and discusses the potential anticancer, antiproliferative, and cytotoxic agents based on the types of secondary metabolites, such as terpenoids, phenolic compounds, alkaloids, steroids, and lignans. Among the anticancer secondary metabolites reported in this review, only few have been isolated from plants that are originated and collected in Ethiopia, and the majority of compounds are reported from plants belonging to different areas of the world. Thus, based on the available bioactivity reports, extensive and more elaborate ethnopharmacology-based bioassay-guided studies have to be conducted on selected traditionally claimed Ethiopian anticancer plants, which inherited from a unique and diverse landscape, with the aim of opening a way forward to conduct anticancer drug discovery program.

Palladium(II)-η3 -Allyl Complexes Bearing N-Trifluoromethyl N-Heterocyclic Carbenes: A New Generation of Anticancer Agents that Restrain the Growth of High-Grade Serous Ovarian Cancer Tumoroids.

The first palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η3 -allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02-0.5 μm). By choosing 1,3,5-triaza-7-phosphaadamantane (PTA) as co-ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2-methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3 -allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids.

Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches

A series of diarylurea derivatives comprising 2,4-diarylpyrimidines were synthesized based on a combination of postulated molecular hybridization design and failed-ligands repurposing approaches, which enabled the discovery of novel potential antiproliferative agents. Towards credible biological evaluation, an in vitro anticancer activity assay was conducted employing a library of 60 cancer cell lines constituting nine panels representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. The results revealed high effectiveness and broad-spectrum anticancer activity of compounds 4m and 4g. Five-dose assay of compounds 4m and 4g proved their high potency that surpassed that of four standard kinase inhibitors FDA-approved anticancer drugs against many cancer cells. Towards the identification of their molecular target, screening of kinase inhibitory profile employing a panel of 51 kinases involved in cancer revealed inhibition of several kinases from the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) kinase family, which might mediate, at least in part, the antiproliferative activity. Molecular docking of 4g into the crystal structure of the Feline McDonough Sarcoma (FMS) kinase predicted that it binds to a pocket formed by the juxtamembrane domain, the catalytic loop, and the αE helix, thus stabilizing the inhibited conformation of the kinase. Flow cytometric study of the cytotoxic effects of compound 4g in A549 cells showed it induces dose- and time-dependent apoptotic events leading to cell death. Collectively, this work presents compound 4g as a potential broad-spectrum anticancer agent against multiple cancer types.

Design and Synthesis of 4(1H)-quinolone Derivatives as Autophagy Inducing Agents by Targeting ATG5 Protein

Background: Quinolines have been characterized as a class of potential antitumor agents, and a large number of natural and synthetic quinolines acting as antitumor agents were reported. Methods: A series of 7-chloro-4(1H)-quinolone derivatives were synthesized. The antiproliferative effect of these compounds was evaluated by MTT assay against five human tumor cell lines. The mechanism of action of the selected compound 7h was also investigated. Results and Discussion: Most of the compounds had more potent antiproliferative activities than the lead compound 7-chloro-4(1H)-quinolone 6b. Compound 7h was found to be the most potent antiproliferative agent against human tumor cell lines. Further investigation demonstrated that compound 7h triggered ATG5-dependent autophagy of colorectal cancer cells by promoting the functions of LC3 proteins. Conclusion: These results were useful for designing and discovering more potent novel antitumor agents endowed with better pharmacological profiles.

Diacetoxy iodobenzene mediated regioselective synthesis and characterization of novel [1,2,4]triazolo[4,3-a]pyrimidines: apoptosis inducer, antiproliferative activities and molecular docking studies

Prompt and regioselective synthesis of eleven novel [1,2,4]triazolo[4,3-a]pyrimidines 2a-2k, via intramolecular oxidative-cyclization of 2-(2-arylidenehydrazinyl)-4-methyl-6-phenylpyrimidine derivatives 1a-1k has been demonstrated here using diacetoxy iodobenzene (DIB) as inexpensive and ecofriendly hypervalent iodine(III) reagent in CH2Cl2 at room temperature. Regiochemistry of final product has been established by developing single crystal and studied X-ray crystallographic data for two derivatives 2c and 2h without any ambiguity. These prominent [1,2,4]triazolo[4,3-a]pyrimidines were evaluated for human osteosarcoma bone cancer (MG-63) and breast cancer (MCF-7) cell lines using MTT assay to find potent antiproliferative agent and also on testicular germ cells to find potent apoptotic inducing activities. All compounds show significant cytotoxicity, particularly 3-(2,4-dichlorophenyl)-5-methyl-7-phenyl-[1,2,4]triazolo[4,3-a]pyrimidine (2g) was found significant apoptotic inducing molecule, as well as the most potent cytotoxic agent against bone cancer (MG-63) and breast cancer (MCF-7) cell lines with GI50 value 148.96 µM and 114.3 µM respectively. Molecular docking studies has been carried out to see the molecular interactions of synthesized compounds with the protein thymidylate synthase (PBD ID: 2G8D). Communicated by Ramaswamy H. Sarma

Rapamycin restrains platelet procoagulant responses via FKBP-mediated protection of mitochondrial integrity

Background and PurposeRapamycin is a potent immunosuppressant and anti-proliferative agent used clinically to prevent organ transplant rejection and for coating coronary stents to counteract restenosis. Rapamycin complexes with the immunophilin FKBP12, which subsequently binds and inhibits mTORC1. Despite several reports demonstrating that rapamycin affects platelet-mediated responses, the underlying mechanism of how it alters platelet function is poorly characterised. This study aimed to elucidate the effect of rapamycin on platelet procoagulant responses. Experimental ApproachThe effect of rapamycin on platelet activation and signalling was investigated alongside the catalytic mTOR inhibitors KU0063794 and WYE-687, and the FKBP12-binding macrolide FK506. Key ResultsRapamycin affects platelet procoagulant responses by reducing externalisation of the procoagulant phospholipid phosphatidylserine, formation of balloon-like structures and local generation of thrombin. Catalytic mTOR kinase inhibitors did not alter platelet procoagulant processes, despite having a similar effect as rapamycin on Ca2+ signalling, demonstrating that the effect of rapamycin on procoagulant responses is independent of mTORC1 inhibition and not linked to a reduction in Ca2+ signalling. FK506, which also forms a complex with FKBP12 but does not target mTOR, reduced platelet procoagulant responses to a similar extent as rapamycin. Both rapamycin and FK506 prevented the loss of mitochondria integrity induced by platelet activation, one of the central regulatory events leading to PS externalisation. Conclusions and ImplicationsRapamycin suppresses platelet procoagulant responses by protecting mitochondrial integrity in a manner independent of mTORC1 inhibition. Rapamycin and other drugs targeting FKBP immunophilins could aid the development of novel complementary anti-platelet therapies.

SPH3643: A novel cyclin-dependent kinase 4/6 inhibitor with good anticancer efficacy and strong blood-brain barrier permeability.

The cyclin‐dependent kinase (CDK)4/6‐cyclin D1‐Rb‐p16/ink4a pathway is responsible for regulating cell progression past the G1 restriction point during the cell cycle. The development of a majority of human tumors is associated with dysregulation of this pathway, resulting in increased cancer cell proliferation. Both CDK4 and CDK6, well‐validated cancer drug targets, function primarily as catalytic enzymes that mediate the phosphorylation of retinoblastoma protein (Rb). Here, we determined that SPH3643 is a novel potent antiproliferative agent that inhibits CDK4/6 kinase activity. In biochemical assays, SPH3643 showed more potent inhibition of both CDK4 and CDK6 than did 2 published CDK4/6 inhibitors, LY2835219 and palbociclib, and had better selectivity than LY2835219. Further in vitro study revealed that SPH3643 blocked Cdk/Rb signaling by inhibiting the phosphorylation of RbSer780 and arrested the MCF‐7 cancer cells at G0/G1 phase, resulting in marked inhibition of the proliferation of Rb‐positive cancer cell lines. In vivo SPH3643 treatment in mice bearing xenograft tumor models of breast cancer, colon cancer, acute myelocytic leukemia, and glioblastoma resulted in significant decreases in tumor growth. SPH3643 was able to particularly strongly inhibit glioblastoma (U87‐MG) cell growth in the brains of orthotopic carcinoma xenograft mice due to its high degree of intracerebral penetration and significant persistence in this setting. Together these results revealed that SPH3643 is a potent, orally active small‐molecule inhibitor of CDK4/6 with robust anticancer efficacy and a high degree of blood‐brain barrier permeability.

A-ring and E-ring modifications of the cytotoxic alkaloid Luotonin A: Synthesis, computational and biological studies

A series of new Luotonin A derivatives with substituents at rings A and E was synthesized, together with some E-ring-unsubstituted derivatives. Subsequently, the compound library was examined in silico for their binding into a previously proposed site in the DNA/topoisomerase I binary complex. Whereas no convincing correlation between docking scores and biological data from in vitro assays could be found, one novel 4,9-diamino Luotonin A derivative had strong antiproliferative activity based on massive G2/M phase arrest. As this biological activity clearly differs from the reference compound Camptothecin, this strongly indicates that at least some Luotonin A derivatives may be potent antiproliferative agents, however with a different mode of action.