New Synthetic Methodologies for the Construction and Optimization of Natural Products

Toxicity associated with bioactive natural products is considered as a major obstacle in the process of drug discovery. Manzamine A (MA) is one such candidate that requires optimization to overcome the toxicity problem. The manzamine alkaloids represents a unique class of natural products that have shown a diverse range of bioactivities including antimicrobial, antiparasitic, cytotoxicity, anti-inflammatory, pesticidial, and was shown to possess activity against HIV-1 and AIDS opportunistic infections. The greatest potential for the manzamine alkaloids appears to be against malaria and neuroinflammation. Experimental and modeling studies suggested that the planer ?-carboline moiety can act as DNA intercalator and hence induce toxicity. Thus either modification or the replacement of the ?-carboline moiety with other heterocycles could eliminate DNA intercalation and will be a huge step forward for generating manzamine-like analogs with similar or better biological activities and reduced toxicity. Using an optimized purification approach that utilized an acid-base treatment of the acetone extract of the Indonesian sponge Acanthostrongylophora sp., 100 g scale of pure manzamine A and 8-hydroxymanzamine A were obtained. Further purification of the more polar fractions led to the isolation of the known manzamines: manzamine F, 12,34-oxamanzamine E, 31-keto-12,34-oxa-32,33-dihydroircinal A, along with two new manzamine-related analogs, acantholactone with unprecedented ?-lactone and 2,21,28-trioxomanzamine J. Twenty manzamine A amides were synthesized through the nitration, reduction and acylation of C-6 and C-8 of the ?-carboline moiety. These analogs were evaluated for in vitro antimalarial and antimicrobial activities. The amides of MA shosignificantly reduced cytotoxicity against Vero cells, although were less active than MA. Two amides 6-cyclohexyamidomanzamine A and 8-n-hexamidomanzamine A shopotent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of these analogs at the dose of 30 mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity. Aminomanzmaines were observed to be unstable in solution and this instability affected the yield of the amides. This instability inspired the development of a simple and practical approach for the one-pot conversion of nitroarenes into amide derivatives. HOAc/Zn were utilized as a reducing agent and acyl chloride/Et3N were used as the acylating agent in DMF with good yield (?60%) of the amide. This method was applicable to 6-nitromanzamine A, where the yield of 6-cyclohexamidemanzamine A was significantly improved (56%) by this approach relative to starting with 6-aminomanzamine A (17%). N-Alkylation of the aminomanzamines was also problematic because of the instability issue. Utilizing the same reducing system (HOAc/Zn), a simple, mild, cost effective, and green approach for the reductive mono N-alkylation of nitroarenes was developed. Carbonyl compounds were utilized as the alkyl source in methanol. Excellent yields were obtained with stoichiometric control of mono over dialkylated products. In order to show the general applicability of our optimized conditions, five natural products: harmane, estradiol, quinine, manzamine F and curcudiol were nitrated and modified using our green N-alkylation strategy. Our new reductive alkylation conditions were well tolerated by the nitrated natural products and afforded moderate to excellent yields. The straightforward oxidation of ircinal A to ircinoic acid inspired utilizing the decarboxylative cross coupling (DCC) approach for the replacement of the ?-carboline moiety with other heterocycles. Optimization of the DCC reaction was completed using (S)-perrilic acid as a model compound; however, failed with ircinoic acid. We then switched to generate the ircinal derived triflate and Suzuki coupling approach. Our proposed scheme was based on the Birch reduction of ircinal A folloby an oxidative deformylation that should generate the corresponding oxo derivative that could be converted to the derived triflate. New and unexpected sequences of reactions were observed in the Birch reduction of ircinal A under atmospheric air. A sequential Birch reduction-elimination-oxidative deformylation were occurred and yielded the unexpected ircinal-derived enone. Further optimizations are needed to convert the new enone to the corresponding triflate

New One-Pot Methodologies for the Modification or Synthesis of Alkaloid Scaffolds

There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative synthetic methodologies to simplify the synthesis of complex molecules. Various classes of natural product alkaloids are both common and widely distributed in plants, bacteria, fungi, insects and marine organisms. This mini-review will discuss the scope, mechanistic insights and enantioselectivity aspects of selected examples of recently developed one-pot methods that have been published in 2009 for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and γ-lactams. In addition, progress on the synthesis of β-carboline (manzamine) alkaloids will also be discussed

Human migration: the big data perspective

How can big data help to understand the migration phenomenon? In this paper, we try to answer this question through an analysis of various phases of migration, comparing traditional and novel data sources and models at each phase. We concentrate on three phases of migration, at each phase describing the state of the art and recent developments and ideas. The first phase includes the journey, and we study migration flows and stocks, providing examples where big data can have an impact. The second phase discusses the stay, i.e. migrant integration in the destination country. We explore various data sets and models that can be used to quantify and understand migrant integration, with the final aim of providing the basis for the construction of a novel multi-level integration index. The last phase is related to the effects of migration on the source countries and the return of migrants

Reductive <i>N</i>-Alkylation of Nitroarenes: A Green Approach for the <i>N</i>‑Alkylation of Natural Products

A simple, mild, cost-effective, and green approach for the reductive mono-<i>N</i>-alkylation of nitroarenes has been developed. HOAc/Zn are utilized as the reducing system together with a carbonyl compound as an alkyl source in methanol. Excellent yields were obtained with stoichiometric control of mono- over dialkylated products. Application to five complex natural products demonstrated the practical utility of the method

An α-selective, visible light photocatalytic glycosylation of alcohols with selenoglycosides

Exceptionally mild procedures for the visible light photocatalytic activation of selenoglycoside donors in the presence of alcohol acceptors have been developed. This process is demonstrated with both 1-phenylselenyl-2,3,4,6- tetra-O-benzyl glucoside (1) and 1-phenylselenyl-2,3,4,6-tetra-O-benzyl galactoside (2). Catalysis is effected with both metal (Ru(bpy)3) and organocatalysts (diphenyldiselenide). Reactions afford, in all cases, primarily the α-anomers with selectivities that vary with solvent. This represents the first example of a visible light-promoted O-glycosylation. © 2013 Elsevier Inc. All rights reserved

An α-selective, visible light photocatalytic glycosylation of alcohols with selenoglycosides

Exceptionally mild procedures for the visible light photocatalytic activation of selenoglycoside donors in the presence of alcohol acceptors have been developed. This process is demonstrated with both 1-phenylselenyl-2,3,4,6- tetra-O-benzyl glucoside (1) and 1-phenylselenyl-2,3,4,6-tetra-O-benzyl galactoside (2). Catalysis is effected with both metal (Ru(bpy)3) and organocatalysts (diphenyldiselenide). Reactions afford, in all cases, primarily the α-anomers with selectivities that vary with solvent. This represents the first example of a visible light-promoted O-glycosylation. © 2013 Elsevier Inc. All rights reserved

Slow-Binding Inhibition of <i>Mycobacterium tuberculosis</i> Shikimate Kinase by Manzamine Alkaloids

Tuberculosis represents a significant public health crisis. There is an urgent need for novel molecular scaffolds against this pathogen. We screened a small library of marine-derived compounds against shikimate kinase from <i>Mycobacterium tuberculosis</i> (<i>Mt</i>SK), a promising target for antitubercular drug development. Six manzamines previously shown to be active against <i>M. tuberculosis</i> were characterized as <i>Mt</i>SK inhibitors: manzamine A (<b>1</b>), 8-hydroxymanzamine A (<b>2</b>), manzamine E (<b>3</b>), manzamine F (<b>4</b>), 6-deoxymanzamine X (<b>5</b>), and 6-cyclohexamidomanzamine A (<b>6</b>). All six showed mixed noncompetitive inhibition of <i>Mt</i>SK. The lowest <i>K</i>_I values were obtained for <b>6</b> across all <i>Mt</i>SK–substrate complexes. Time-dependent analyses revealed two-step, slow-binding inhibition. The behavior of <b>1</b> was typical; initial formation of an enzyme–inhibitor complex (EI) obeyed an apparent <i>K</i>_I of ∼30 μM with forward (<i>k</i>₅) and reverse (<i>k</i>₆) rate constants for isomerization to an EI* complex of 0.18 and 0.08 min^–1, respectively. In contrast, <b>6</b> showed a lower <i>K</i>_I for the initial encounter complex (∼1.5 μM), substantially faster isomerization to EI* (<i>k</i>₅ = 0.91 min^–1), and slower back conversion of EI* to EI (<i>k</i>₆ = 0.04 min^–1). Thus, the overall inhibition constants, <i>K</i>_I*, for <b>1</b> and <b>6</b> were 10 and 0.06 μM, respectively. These findings were consistent with docking predictions of a favorable binding mode and a second, less tightly bound pose for <b>6</b> at <i>Mt</i>SK. Our results suggest that manzamines, in particular <b>6</b>, constitute a new scaffold from which drug candidates with novel mechanisms of action could be designed for the treatment of tuberculosis by targeting <i>Mt</i>SK