Browsing by Author "Nicolaou, K.C."
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Item Cyclic Marinopyrrole Derivatives as Disruptors of Mcl-1 and Bcl-xL Binding to Bim(MDPI, 2014) Cheng, Chunwei; Liu, Yan; Balasis, Maria E.; Simmons, Nicholas L.; Li, Jerry; Song, Hao; Pan, Lili; Qin, Yong; Nicolaou, K.C.; Sebti, Said M.; Li, RongshiA series of novel cyclic marinopyrroles were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Both atropisomers of marinopyrrole A (1) show similar potency. A tetrabromo congener 9 is two-fold more potent than 1. Two novel cyclic marinopyrroles (3 and 4) are two- to seven-fold more potent than 1.Item Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim(MDPI, 2014) Cheng , Chunwei; Liu, Yan; Balasis, Maria E.; Garner, Thomas P.; Li, Jerry; Simmons, Nicholas L.; Berndt, Norbert; Song, Hao; Pan, Lili; Qin, Yong; Nicolaou, K.C.; Gavathiotis, Evripidis; Sebti , Said M.; Li, Rongshi; BioScience Research CollaborativeA series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl- and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC50 values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation.Item Microsphere-based immunoassay for the detection of azaspiracids(Elsevier, 2014) Rodríguez, Laura P.; Vilariño, Natalia; Louzao, M. Carmen; Dickerson, Tobin J.; Nicolaou, K.C.; Frederick, Michael O.; Botana, Luis M.; BioScience Research CollaborativeAzaspiracids (AZAs) are a group of lipophilic toxins discovered in mussels from Ireland in 1995 following a human poisoning incident. Nowadays the regulatory limit for AZAs in many countries is set at 160 μg of azaspiracid equivalents per kilogram of shellfish meat. In this work a microsphere-based immunoassay has been developed for the detection of AZAs using a Luminex system. This method is based on the competition between AZA-2 immobilized onto the surface of microspheres and free AZAs for the interaction with a monoclonal anti-azaspiracid antibody (mAb 8F4). In this inhibition immunoassay the amount of mAb 8F4 bound to AZA-2 microspheres was quantified using a phycoerythrin-labeled anti-mouse antibody, and the fluorescence was measured with a Luminex analyzer. Simple acetate/methanol or methanol extractions yielded final extracts with no matrix interferences and adequate recovery rates of 86.5 and 75.8%, respectively. In summary, this work presents a sensitive and easily performed screening method capable of detecting AZAs at concentrations below the range of the European regulatory limit using a microsphere/flow cytometry system.Item Organic synthesis: the art and science of replicating the molecules of living nature and creating others like them in the laboratory(Royal Society Publishing, 2014) Nicolaou, K.C.; BioScience Research CollaborativeSynthetic organic chemists have the power to replicate some of the most intriguing molecules of living nature in the laboratory and apply their developed synthetic strategies and technologies to construct variations of them. Such molecules facilitate biology and medicine, as they often find uses as biological tools and drug candidates for clinical development. In addition, by employing sophisticated catalytic reactions and appropriately designed synthetic processes, they can synthesize not only the molecules of nature and their analogues, but also myriad other organic molecules for potential applications in many areas of science, technology and everyday life. After a short historical introduction, this article focuses on recent advances in the field of organic synthesis with demonstrative examples of total synthesis of complex bioactive molecules, natural or designed, from the author's laboratories, and their impact on chemistry, biology and medicine.Item Synthesis and Biological Evaluation of QRSTUVWXYZA' Domains of Maitotoxin(American Chemical Society, 2014) Nicolaou, K.C.; Heretsch, Philipp; Nakamura, Tsuyoshi; Rudo, Anna; Murata, Michio; Konoki, Keiichi; BioScience Research CollaborativeThe synthesis of QRSTUVWXYZA′ domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai–Utimoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner–Wadsworth–Emmons coupling of WXYZA′ ketophosphonate 11 with QRSTU aldehyde 12 to form enone 10, and a reductive hydroxyketone ring closure to forge ring V. 2D NMR spectroscopic analysis and comparison of 13C chemical shifts with those of the corresponding carbons of maitotoxin revealed close similarities supporting the originally assigned structure of this region of the natural product. Biological evaluations of various synthesized domains of maitotoxin in this and previous studies from these laboratories led to fragment structure–activity relationships regarding their ability to inhibit maitotoxin-elicited Ca2+ influx in rat C6 glioma cells.Item The Emergence of the Structure of the Molecule and the Art of Its Synthesis(Wiley, 2013) Nicolaou, K.C.At the core of the science of chemistry lie the structure of the molecule, the art of its synthesis, and the design of function within it. These attributes elevate chemistry to an essential, indispensable, and powerful discipline whose impact on the life and materials sciences is paramount, undisputed, and expanding. Indeed, today the combination of structure, synthesis, and function is driving many scientific frontiers forward, including drug discovery and development, biology and biotechnology, materials science and nanotechnology, and molecular devices of all kinds. What connects structure and function is synthesis, whose flagship is total synthesis, the art of constructing the molecules of nature and their derivatives. The power of chemical synthesis at any given time is reflected and symbolized by the state of the art of total synthesis, and as such the condition and sophistication of the latter needs to be continuously nourished and advanced. In this review the understanding of the structure of the molecule, the emergence of organic synthesis, and the art of total synthesis are traced from the nineteenth century to the present day.Item The endeavor of total synthesis and its impact on chemistry, biology and medicine(Oxford University Press, 2014) Nicolaou, K.C.; Hale, Christopher R.H.; BioScience Research CollaborativeThe synthesis of urea in 1828 set in motion the discipline of organic synthesis in general and of total synthesis in particular, the art and science of synthesizing natural products, the molecules of living nature. Early endeavors in total synthesis had as their main objective the proof of structure of the target molecule. Later on, the primary goal became the demonstration of the power of synthesis to construct complex molecules through appropriately devised strategies, making the endeavor an achievement whose value was measured by its elegance and efficiency. While these objectives continue to be important, contemporary endeavors in total synthesis are increasingly focused on practical aspects, including method development, efficiency, and biological and medical relevance. In this article, the emergence and evolution of total synthesis to its present state is traced, selected total syntheses from the author's laboratories are highlighted, and projections for the future of the field are discussed.Item Total Synthesis and Structural Revision of Antibiotic CJ-16,264(Wiley, 2015) Nicolaou, K.C.; Shah, Akshay A.; Korman, Henry; Khan, Tabrez; Shi, Lei; Worawalai, Wisuttaya; Theodorakis, Emmanuel A.; BioScience Research CollaborativeThe total synthesis and structural revision of antibiotic CJ-16,264 is described. Starting with citronellal, the quest for the target molecule featured a novel bis-transannular Diels-Alder reaction that casted stereoselectively the decalin system and included the synthesis of six isomers before demystification of its true structure.Item Total Synthesis of Myceliothermophins C, D and E(Wiley, 2014) Nicolaou, K.C.; Shi, Lei; Lu, Min; Pattanayak, Manas R.; Shah, Akshay A.; Ioannidou, Heraklidia A.; Lamani, Manjunath; BioScience Research CollaborativeThe total synthesis of cytotoxic polyketides myceliothermophins E (1), C (2) and D (3) through a cascade-based cyclization to form the trans-fused decalin system is described. The convergent synthesis delivered all three natural products through late-stage divergence and facilitated unambiguous C21 structural assignments for 2 and 3 through X-ray crystallographic analysis which revealed an interesting dimeric structure between its enantiomeric forms.Item Total Synthesis of Viridicatumtoxin B and Analogues Thereof: Strategy Evolution, Structural Revision, and Biological Evaluation(American Chemical Society, 2014) Nicolaou, K.C.; Hale, Christopher R.H.; Nilewski, Christian; Ioannidou, Heraklidia A.; ElMarrouni, Abdelatif; Nilewski, Lizanne G.; Beabout, Kathryn; Wang, Tim T.; Shamoo, YousifThe details of the total synthesis of viridicatumtoxin B (1) are described. Initial synthetic strategies toward this intriguing tetracycline antibiotic resulted in the development of key alkylation and Lewis acid-mediated spirocyclization reactions to form the hindered EF spirojunction, as well as Michael-Dieckmann reactions to set the A and C rings. The use of an aromatic A-ring substrate, however, was found to be unsuitable for the introduction of the requisite hydroxyl groups at carbons 4a and 12a. Applying these previous tactics, we developed stepwise approaches to oxidize carbons 12a and 4a based on enol- and enolate-based oxidations, respectively, the latter of which was accomplished after systematic investigations that revealed critical reactivity patterns. The herein described synthetic strategy resulted in the total synthesis of viridicatumtoxin B (1), which, in turn, formed the basis for the revision of its originally assigned structure. The developed chemistry facilitated the synthesis of a series of viridicatumtoxin analogues, which were evaluated against Gram-positive and Gram-negative bacterial strains, including drug-resistant pathogens, revealing the first structure-activity relationships within this structural type.Item Total Synthesis of Δ12-Prostaglandin J3, a Highly Potent and Selective Antileukemic Agent(Wiley, 2014) Nicolaou, K.C.; Heretsch, Philipp; ElMarrouni, Abdelatif; Hale, Christopher R.H.; Pulukuri, Kiran K.; Kudva, Avinash K.; Narayan, Vivek; Prabhu, K. Sandeep; BioScience Research CollaborativeA catalytic asymmetric total synthesis of the potent and selective antileukemic Δ12-prostaglandin J3 (Δ12-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, constructed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.