Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers.

Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O6-alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O6-(2-fluoroethyl)guanine (O6FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O6-ethanoguanine (N1,O6EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O6EtG formation allows healthy cells expressing MGMT to reverse the initial O6FEtG lesion before it evolves to N1,O6EtG, thereby suppressing the formation of toxic DNA-MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O6-(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O6EtG, resulting in the formation of DNA-MGMT cross-links and DNA ICLs in healthy tissue. These studies suggest that careful consideration of the rates of chemical DNA modification and biochemical DNA repair may lead to the identification of other tumor-specific genotoxic agents.

De Novo Synthesis of an l-Lemonose Thioglycoside Donor from d-Threonine.

A short de novo synthesis of an l-lemonose thioglycoside is described starting from d-threonine. The synthesis leverages a Dieckmann condensation and Stork-Danheiser transposition to arrive at a key vinylogous ester intermediate on gram scale. Ensuing 1,2-addition diastereoselectively establishes the C3 tetra-substituted center and subsequent glycal hydration allows for anomeric functionalization to the thioglycoside. 1H and NOESY NMR analyses reveal that the major α-anomer of thioglycoside deviates from the expected 1C4 conformation.

Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists.

Herein, we report the synthesis and structure-activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1µM against D1, D2L, D2S, D3, and D5).

Mechanism-based design of agents that selectively target drug-resistant glioma.

Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O6-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.

Synthesis and Cytotoxic Evaluation of Arimetamycin A and Its Daunorubicin and Doxorubicin Hybrids.

The arimetamycin A glycan governs the compound's cytotoxicity (IC50). To study this branched, deoxy-amino disaccharide, we designed and synthesized a modified acyl donor that underwent glycosylation with three anthracycline aglycones: steffimycinone, daunorubicinone, and doxorubicinone. The result of the approach was a synthesis of arimetamycin A and two novel hybrid anthracyclines. Each molecule exhibited enhanced cytotoxicity in comparison to the parent anthracyclines, steffimycin B, daunorubicin, and doxorubicin. An orienting mechanistic evaluation revealed that the daunorubicin hybrid inhibits the ability of human topoisomerase IIα to relax negatively and positively supercoiled DNA.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Luteolin Decreases Epidermal Growth Factor Receptor-Mediated Cell Proliferation and Induces Apoptosis in Glioblastoma Cell Lines.

Glioblastomas are a subtype of gliomas, which are the most aggressive and deadly form of brain tumours. The epidermal growth factor receptor (EGFR) is over-expressed and amplified in glioblastomas. Luteolin is a common bioflavonoid found in a variety of fruits and vegetables. The aim of this study was to explore the molecular and biological effects of luteolin on EGF-induced cell proliferation and the potential of luteolin to induce apoptosis in glioblastoma cells. In vitro cell viability assays demonstrated that luteolin decreased cell proliferation in the presence or absence of EGF. Immunoblots revealed that luteolin decreased the protein expression levels of phosphorylated Akt, mTOR, p70S6K and MAPK in the presence of EGF. Furthermore, our results revealed the ability of luteolin to induce caspase and PARP cleavages in glioblastoma cells in addition to promoting cell cycle arrest. Our results demonstrated that luteolin has an inhibitory effect on downstream signalling molecules activated by EGFR, particularly the Akt and MAPK signalling pathways, and provided a rationale for further clinical investigation into the use of luteolin as a therapeutic molecule in the management of glioblastoma.

The antiproliferative and apoptotic effects of apigenin on glioblastoma cells.

OBJECTIVES: Glioblastoma (GBM) is highly proliferative, infiltrative, malignant and the most deadly form of brain tumour. The epidermal growth factor receptor (EGFR) is overexpressed, amplified and mutated in GBM and has been shown to play key and important roles in the proliferation, growth and survival of this tumour. The goal of our study was to investigate the antiproliferative, apoptotic and molecular effects of apigenin in GBM. METHODS: Proliferation and viability tests were carried out using the trypan blue exclusion, MTT and lactate dehydrogenase (LDH) assays. Flow cytometry was used to examine the effects of apigenin on the cell cycle check-points. In addition, we determined the effects of apigenin on EGFR-mediated signalling pathways by Western blot analyses. KEY FINDINGS: Our results showed that apigenin reduced cell viability and proliferation in a dose- and time-dependent manner while increasing cytotoxicity in GBM cells. Treatment with apigenin-induced is poly ADP-ribose polymerase (PARP) cleavage and caused cell cycle arrest at the G2M checkpoint. Furthermore, our data revealed that apigenin inhibited EGFR-mediated phosphorylation of mitogen-activated protein kinase (MAPK), AKT and mammalian target of rapamycin (mTOR) signalling pathways and attenuated the expression of Bcl-xL. CONCLUSION: Our results demonstrated that apigenin has potent inhibitory effects on pathways involved in GBM proliferation and survival and could potentially be used as a therapeutic agent for GBM.