Natural Product Derivatives Research Articles

Total Synthesis and Antibiotic Properties of Amino‐Functionalized Aromatic Terpenoids Related to Erogorgiaene and the Pseudopterosins

AbstractFollowing a concept recently introduced by Hergenrother,[6] the present study addresses the question of whether certain antimicrobially active aromatic (marine) natural products can be converted into more potent broad‐spectrum antibiotics by introducing an aminoalkyl side chain. To this end, phenolic mono‐ and sesquiterpenoids (incl. carvacrol, xanthorrhizol, and 7‐hydroxycalamene) as well as the diterpenes 7‐hydroxyerogorgiaene and 9‐deoxypseudopterosin A were converted into amino‐functionalized analogs that display either an amino‐methyl or a 2‐amino‐ethoxy substituent in place of (or next to) the OH group. This was achieved either by Pd‐catalyzed nitromethylation/reduction of the aryltriflates, by O‐alkylation of the phenols with bromoacetonitrile and subsequent reduction, or by ortho‐hydroxymethylation/amination. During the study, an efficient enantioselective total synthesis of 7‐hydroxyerogorgiaene (8 steps, 29 % overall yield) and 9‐deoxypseudopterosin A (9 steps, 30 % overall yield) was elaborated using an asymmetric cobalt‐catalyzed hydrovinylation (91 % ee) of 3‐methoxy‐4‐methyl‐styrene as the chirogenic step. Other important C−C bond forming steps include a Pd‐catalyzed Suzuki cross‐coupling and diastereoselective Lewis acid‐mediated cyclization reactions. A total of 16 amino derivatives of natural products were prepared and subsequently tested for their antibacterial properties. Some of the diterpene‐derived amines showed high efficacy, not only against Gram‐positive (S. aureus SG511, S. aureus HG003, B. subtilis 168; MIC=0.5 to 2 μg/ml), but also against Gram‐negative bacterial strains (E. coli K12; E. coli I‐11276b; MIC=8 to 32 μg/ml). This clearly supported the underlying working hypothesis.

Excited-State Palladium-Catalyzed Radical Migratory Mizoroki-Heck Reaction Enables C2-Alkenylation of Carbohydrates.

Excited-state palladium catalysis has emerged as a promising strategy for developing novel and valuable reactions. Herein, we report the first excited-state Pd-catalyzed 1,2-radical migratory Mizoroki-Heck reaction that enables C2-alkenylation of carbohydrates using readily available 1-bromosugars and alkenes. The reaction tolerates a wide variety of functional groups and complex molecular architectures, including derivatives of natural products and marketed drugs. Preliminary mechanistic studies and DFT calculations suggest the involvement of visible-light-induced photoexcitation of Pd species, 1,2-spin-centered-shift (SCS) process, and Heck-type cross-coupling reaction. The reaction expands the reactivity profile of excited-state Pd catalysis and provides a streamlined protocol for the preparation of a wide variety of C2-alkenylated carbohydrate mimetics to aid the discovery and development of new therapeutics, agrochemicals, and materials.

Bioinspired desaturation of alcohols enabled by photoredox proton-coupled electron transfer and cobalt dual catalysis

In the biosynthesis sterols an enzyme-catalyzed demethylation is achieved via a stepwise oxidative transformation of alcohols to olefins. The overall demethylation proceeds through two sequential monooxygenation reactions and a subsequent dehydroformylative saturation. To mimic the desaturation processes observed in nature, we have successfully integrated photoredox proton-coupled electron transfer (PCET) and cobaloxime chemistry for the acceptorless dehydrogenation of alcohols. The state-of-the-art remote and precise desaturation of ketones proceeds efficiently through the activation of cyclic alcohols using bond-dissociation free energy (BDFE) as thermodynamic driving force. The resulting transient alkoxyl radical allows C-C bond scission to generate the carbon-centered radical remote to the carbonyl moiety. This key intermediate is subsequently combined with cobaloxime photochemistry to furnish the alkene. Moreover, the mild protocol can be extended to desaturation of linear alcohols as well as aromatic hydrocarbons. Application to bioactive molecules and natural product derivatives is also presented.

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues.

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Merging enzymes with chemocatalysis for amide bond synthesis

Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. Despite this, there is a need for more sustainable amide synthesis. Herein, we report an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds. This synergistic one-pot combination of chemo- and biocatalysis provides an amide bond disconnection to precursors, that are orthogonal to those in classical amide synthesis, obviating the need for protecting groups and delivering amides in a manner unachievable using existing catalytic regimes. Our integrated approach also affords broad scope, very high (molar) substrate loading, and has excellent functional group tolerance, telescoping routes to natural product derivatives, drug molecules, and challenging chiral amides under environmentally friendly conditions at scale.

AIE-based gold nanostar-berberine dimer nanocomposites for PDT and PTT combination therapy toward breast cancer.

We designed and synthesized three new berberine-based compounds, namely, pyridine-2,6-dimethyl-/2,2'-bipyridine-3,3'-dimethyl-tethered berberine dimers BD1 and BD2, and a tetrakis(4-benzyl)ethylene linked berberine tetramer BD4. We identified that the dimer BD2 and tetramer BD4, as well as 1,10-phenanthroline-2,9-dimethyl-linked berberine dimer BD3 previously reported by us, showed remarkable aggregation-induced emission (AIE) properties which endowed them with higher singlet oxygen (1O2) production ability than berberine. Of the four compounds, BD3 exhibits the lowest ΔEST energy with the highest 1O2 generation ability and thus was selected for further construction of AuNSs-BD3@HA (denoted as ABH, AuNSs = gold nanostars; HA = hyaluronic acid). The nanosystem of ABH shows a remarkable therapeutic effect toward breast cancer by combining photodynamic therapy (PDT) from BD3, photothermal therapy (PTT) from AuNSs, and the CD44-targeting capability of HA. The synergistically enhanced PDT and PTT induce superior cancer cell apoptosis/necrosis in vitro and anti-breast cancer activity in vivo. This study provides a new concept for PDT using natural product derivatives and their combination with PTT for efficient treatment of tumors.

Lipase-Catalyzed Site-Selective Deacetylation of 2-Methoxy-3-methylnaphthalene-1,4-diol Diacetate for Construction of Characteristic Substituted 1,2,3,4-Tetrahydroisoquinoline Derivative of Novel Ecteinascidin Marine Natural Product

Lipase-Catalyzed Site-Selective Deacetylation of 2-Methoxy-3-methylnaphthalene-1,4-diol Diacetate for Construction of Characteristic Substituted 1,2,3,4-Tetrahydroisoquinoline Derivative of Novel Ecteinascidin Marine Natural Product

Copper-catalyzed stereo- and regioselective hydrophosphorylation of terminal alkynes: scope and mechanistic study.

Herein, a protocol for copper-catalyzed highly stereo- and regioselective hydrophosphorylation of terminal alkynes to E-alkenylphosphorus compounds was well developed. It represents a general and practical hydrophosphorylation method, of which diarylphosphine oxide, dialkylphosphine oxide and dialkyl phosphite all had effective P(O)H parts to react with different types of terminal alkynes. Contrary to previous air-sensitive reports, all the reactions proceeded well under air. This methodology is quite attractive owing to the high stereo- and regioselectivity, good functional group tolerance, scalability and facile late-stage derivatization of some natural product derivatives and commercially available herbicides. What's more, investigations on the reaction mechanism with deuterium-labeling experiments and DFT studies firstly disclosed the deprotonation–protonation equilibrium of terminal alkynes and P(O)H part during the catalytic hydrophosphorylation process.

Screening of Heartwood of Tectona Grandis Linn for Antifungal Activity

AB S T R A C T Medicinal plants have always been a subject of interest for the human being from ancient times due to health benefits. Researchers found that people in different regions of the world used the same or similar plants for health benefits. Medicinal plant research includes many fields like drug discovery, ethnobotany, traditional and indigenous medicines. During the corona pandemic, we realised that there are no effective therapies available for new and remerging infectious diseases. Public health is badly affected due to drug- resistant microorganisms and the appearance of new disease- causing microbes. Due to the increasing side effects of synthetic drugs and uncontrolled infectious diseases, researchers have taken interest in natural sources of medicines and have screened a large number of plants for new bioactive compounds. Natural products have been a well-known source of various molecules in the process of drug discovery and many bioactive natural product derivatives. Stereochemical and structural properties of natural products are characteristics that are responsible for exploring novel molecular diversity. One of the successful strategies for the investigation of new medicinal agents from plants includes the screening of plant extract, fractions followed by the purification of the constituents. Several plants and their products have been evaluated for their antimicrobial and antioxidant activity. In the present study, the ethanolic extract of the heartwood of Tectona grandis Linn. was screened for antifungal activity

Potential Pharmaceutical Application of Endemic Plants: When will Sri Lanka Understand the Economic Value Chain?

Small molecules has been a main concern in the pharmaceutical industry for as long as they have existed. Enormous libraries of compounds have been collected and they in turn nurture drug discovery research. For example, big pharma, has in their compound libraries ranging from 500,000 to several million. Examining the drugs in the market, it is clear from where most are arriving: natural origin; out of the 1,328 new chemical entities approved as drugs between 1981 and 2016, only 359 were purely of synthetic origin. In the list of remaining ones, 326 were “biologics”, and 94 were vaccines. Importantly, 549 were from natural origin or arose motivated from natural compounds. Furthermore, anticancer compounds arising during the same period (1981–2014), only 23 were purely synthetic (Newman and Cragg, 2016). Natural origin can count for three categories: unaltered natural products; distinct mixture of natural products and natural product derivatives isolated from plants or other living organisms such as fungi, sponges, lichens, or microorganisms; and products modified through application of medicinal chemistry. There are many examples covering a wide spectrum of diseases: anticancer drugs such as docetaxel (Taxotere™), paclitaxel (Taxol™), vinblastine, podophyllotoxin (Condylin™), or etoposide; steroidal hormones such as progesterone, norgestrel, or cortisone; cardiac glycosides such as digitoxigenin; antibiotics like penicillin, streptomycin, and cephalosporins.

Three Rings to Rule Them All: How Versatile Flavoenzymes Orchestrate the Structural Diversification of Natural Products.

The structural diversification of natural products is instrumental to their versatile bioactivities. In this context, redox tailoring enzymes are commonly involved in the modification and functionalization of advanced pathway intermediates en route to the mature natural products. In recent years, flavoprotein monooxygenases have been shown to mediate numerous redox tailoring reactions that include not only (aromatic) hydroxylation, Baeyer–Villiger oxidation, or epoxidation reactions but also oxygenations that are coupled to extensive remodeling of the carbon backbone, which are often central to the installment of the respective pharmacophores. In this Perspective, we will highlight recent developments and discoveries in the field of flavoenzyme catalysis in bacterial natural product biosynthesis and illustrate how the flavin cofactor can be fine-tuned to enable chemo-, regio-, and stereospecific oxygenations via distinct flavin-C4a-peroxide and flavin-N5-(per)oxide species. Open questions remain, e.g., regarding the breadth of chemical reactions enabled particularly by the newly discovered flavin-N5-oxygen adducts and the role of the protein environment in steering such cascade-like reactions. Outstanding cases involving different flavin oxygenating species will be exemplified by the tailoring of bacterial aromatic polyketides, including enterocin, rubromycins, rishirilides, mithramycin, anthracyclins, chartreusin, jadomycin, and xantholipin. In addition, the biosynthesis of tropone natural products, including tropolone and tropodithietic acid, will be presented, which features a recently described prototypical flavoprotein dioxygenase that may combine flavin-N5-peroxide and flavin-N5-oxide chemistry. Finally, structural and mechanistic features of selected enzymes will be discussed as well as hurdles for their application in the formation of natural product derivatives via bioengineering.

Modification of waste persimmon peel and application in water-based drilling fluid

To develop a green drilling fluid additive, the modification and application of persimmon peel in a water-based drilling fluid was studied in this work. A natural product derivative, aluminium chloride–persimmon peel (ACPP), was prepared from aluminium chloride and persimmon peel and was assessed as a shale inhibitor. The clay-swelling ratio in 0.30% ACPP-3 solution was reduced to 28.10% from 69.50%. The rolling recovery tests and rheological evaluation of drilling fluids concluded that ACPP-3 has a high inhibition property to montmorillonite-hydrated expansion. ACPP-3 can adjust the particle size of montmorillonite to a large degree. ACPP-3 effectively reduces the apparent viscosity of carboxymethyl cellulose drilling fluids and the volume of filtration; furthermore, ACPP-3 can reduce the viscosity and the volume of filtration under high temperature, which means it can be used as an additive for deep drilling. The inhibition mechanism of ACPP-3 was investigated by thermogravimetric analysis and scanning electron microscopy. The results of this scientific research will be beneficial to the eco-friendly drilling fluid materials.

Click Chemistry in Natural Product Modification.

Click chemistry is perhaps the most powerful synthetic toolbox that can efficiently access the molecular diversity and unique functions of complex natural products up to now. It enables the ready synthesis of diverse sets of natural product derivatives either for the optimization of their drawbacks or for the construction of natural product-like drug screening libraries. This paper showcases the state-of-the-art development of click chemistry in natural product modification and summarizes the pharmacological activities of the active derivatives as well as the mechanism of action. The aim of this paper is to gain a deep understanding of the fruitful achievements and to provide perspectives, trends, and directions regarding further research in natural product medicinal chemistry.

Host-guest inclusion systems of two bioactive natural products derivantives and three polyamine-modified β-cyclodextrins: Preparation, characterization, biological activity

Two bioactive natural products derivatives including hydroxycamptothecin (HCPT) and etoposide (EPEG), which are one of the most common classes of first-line anticancer drugs used for the treatment of cancer. Of note, their application is still limited by poor water solubility and bioavailability. Therefore, it is very important to develop a new means to solve these shortcomings. In this work, the molecular binding behavior of three polyamine-modified β-cyclodextrins (H1-3) with HCPT and EPEG was investigated. The six novel H1-3/HCPT (EPEG) inclusion complexes were prepared and characterized by Fourier transform infrared spectrometry (FTIR), 2D nuclear magnetic resonance (2D ROESY), 1H nuclear magnetic resonance (NMR), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The phase solubility diagrams indicated that the stability constants (K1:1) of host H1-3 to the free drugs decrease sequentially as follows: H3>H2>H1. After forming inclusion complexes with H1-3, the water solubility of HCPT (EPEG) were obviously increased from the initial value of 0.0011 mg/mL (0.373 mg/mL) to 0.90 mg/mL (32.55 mg/mL), 2.01 mg/mL (38.73 mg/mL), and 2.39 mg/mL (47.42 mg/mL), enhanced by 84.9–225.5 times compared with the free drug, respectively. The in vitro release tests confirmed that the cumulative release of drug from H1-3/EPEG (HCPT) complexes was significantly higher than that from free drug solution in 50 h. The cytotoxicity assay showed that the H1/HCPT exhibited higher cytotoxicity towards MCF-7 cell in comparison to the free drug HCPT. Meanwhile, the toxicity of HCPT is obviously reduced after the formation of H2/HCPT. Apoptosis experiments revealed that the percentage of apoptotic cells was increased by H3/HCPT (65.80%), which close to increasing by free drugs HCPT (74.00%) when the concentrations of H3/HCPT and HCPT reached to a certain level (5.0 μg/mL). The satisfactory water solubility, high activity, and low toxicity of H1-3/HCPT (EPEG) inclusion complexes contributes to research with new applications of the HCPT and EPEG as anticancer drug formulations.

Remote Radical Desaturation of Unactivated C-H Bonds in Amides.

Desaturation of inert aliphatic C−H bonds in alkanes to form the corresponding alkenes is challenging. In this communication, a new and practical strategy for remote site‐selective desaturation of amides via radical chemistry is reported. The readily installed N‐allylsulfonylamide moiety serves as an N radical precursor. Intramolecular 1,5‐hydrogen atom transfer from an inert C−H bond to the N‐radical generates a translocated C‐radical which is subsequently oxidized and deprotonated to give the corresponding alkene. The commercially available methanesulfonyl chloride is used as reagent and a Cu/Ag‐couple as oxidant. The remote desaturation is realized on different types of unactivated sp3‐C−H bonds. The potential synthetic utility of this method is further demonstrated by the dehydrogenation of natural product derivatives and drugs.

Selective Trifluoromethylthiolation of Unactivated C(sp3)−H Bonds Enabled by Excited Ketones

AbstractHere we report that the selective trifluoromethylthiolation of unactivated C(sp3)−H bonds is enabled by photoexcited diaryl ketones. This method for C−H trifluoromethylthiolation features mild conditions and inexpensive organic photocatalysts and relies on 370 nm LED lights. The functional group tolerance is broad and the excellent regioselectivity for branched aliphatic positions enables trifluoromethylthiolation of a variety of substrates, including amino acid and natural product derivatives, demonstrating its potential synthetic application.

Mutasynthesis of Medicinally Significant Natural Products Through Manipulation of Gene Governing Starter Unit

Most of the biologically active microbial natural products and their analogs bear a complex molecular architecture. The semisynthetic modifications and stereospecific diversity- oriented synthesis of these native natural products to generate analogs are difficult and time-consuming. Mutasynthesis is a powerful tool that utilizes the microorganism's genetic and metabolic engineering skills to produce derivatives of complex natural products of microbial origin. Mutasynthesis is based on the cellular uptake of chemically modified intermediates from the culture media and their addition to the secondary metabolism by mutant microorganisms. This review will describe the importance of mutasynthesis in the generation of complex microbial secondary metabolites. We have covered a literature search on mutasynthesis over the last ten years (2011-2020) in this review.

Remote Site-Selective Radical C(sp3 )-H Monodeuteration of Amides using D2 O.

Site‐selective incorporation of deuterium into biologically active compounds is of high interest in pharmaceutical industry. We present a mild and environmentally benign metal‐free method for the remote selective radical C−H monodeuteration of aliphatic C−H bonds in various amides with inexpensive heavy water (D2O) as the deuterium source. The method uses the easily installed N‐allylsulfonyl moiety as an N‐radical precursor that generates the remote C‐radical via site‐selective 1,5‐ or 1,6‐hydrogen atom transfer (HAT). Methyl thioglycolate, that readily exchanges its proton with D2O, serves as the radical deuteration reagent and as a chain‐carrier. The highly site‐selective monodeuteration has been applied to different types of unactivated sp 3‐C−H bonds and also to the deuteration of C−H bonds next to heteroatoms. The potential utility of this method is further demonstrated by the site‐selective incorporation of deuterium into natural product derivatives and drugs.

Remote Site‐Selective Radical C(sp 3 )−H Monodeuteration of Amides using D 2 O

AbstractSite‐selective incorporation of deuterium into biologically active compounds is of high interest in pharmaceutical industry. We present a mild and environmentally benign metal‐free method for the remote selective radical C−H monodeuteration of aliphatic C−H bonds in various amides with inexpensive heavy water (D2O) as the deuterium source. The method uses the easily installed N‐allylsulfonyl moiety as an N‐radical precursor that generates the remote C‐radical via site‐selective 1,5‐ or 1,6‐hydrogen atom transfer (HAT). Methyl thioglycolate, that readily exchanges its proton with D2O, serves as the radical deuteration reagent and as a chain‐carrier. The highly site‐selective monodeuteration has been applied to different types of unactivated sp3‐C−H bonds and also to the deuteration of C−H bonds next to heteroatoms. The potential utility of this method is further demonstrated by the site‐selective incorporation of deuterium into natural product derivatives and drugs.

Chalcone derived benzoheterodiazepines for medicinal applications: A Two‐pot and one‐pot synthetic approach

AbstractThe production of effective drugs has continuously been a challenging process for researchers due to the occurrence of resistive diseases. Drugs derived from natural product‐based compounds as an active scaffold have gained interest in drug development due to a wide range of biological properties. Benzoheterodiazepines, a natural product derivative of bicyclic chalcones have been widely reported with various therapeutic potentials. This review discusses current synthetic methods in the preparation of benzoheterodiazepine derivatives (i.e., homocyclic benzoheterodiazepine, heterocyclic benzoheterodiazepine, bis‐benzoheterodiazepine, and fused benzoheterodiazepine) via two‐pot and one‐pot synthetic routes. Several reaction protocols following both synthetic routes have been developed for efficient and higher yields that offer access to different functionalization of benzoheterodiazepines are comprehensively described. This review is important in the heterocyclic chemistry of benzoheterodiazepines and pharmacological industries in drug development processes.