Polycyclic Derivatives Research Articles

Synthetic Methods for the Preparation of Conformationally Restricted Analogues of Nicotine.

In the context of naturally occurring nitrogen heterocycles, nicotine is a chiral alkaloid present in tobacco plants, which can target and stimulate nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels commonly located throughout the human brain. Due to its well-known toxicity for humans, there is considerable interest in the development of synthetic analogues; in particular, conformationally restricted analogues of nicotine have emerged as promising drug molecules for selective nAChR-targeting ligands. In the present mini-review, we will describe the synthesis of the conformationally restricted analogues of nicotine involving one or more catalytic processes. In particular, we will follow a systematic approach as a function of the heteroarene structure, considering: (a) 2,3-annulated tricyclic derivatives; (b) 3,4-annulated tricyclic derivatives; (c) tetracyclic derivatives; and (d) other polycyclic derivatives. For each of them we will also consider, when carried out, biological studies on their activity for specific nAChR subunits.

Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery.

Heterocyclic amino derivatives have been extensively synthesized and validated as potent bioactive compounds, and nowadays, numerous marketed drugs share these scaffolds, from very simple structures (monoamino, monocyclic compounds) to much more complex molecules (polycyclic derivatives with two or more nitrogen atoms within the (fused) rings). In a constant quest for new chemical entities in drug discovery, a few novel heterocycles have emerged in recent years as promising building blocks for the obtainment of bioactive modulators. In this context, pyrrolotriazinones have attracted attention, and some show promising biological activities. Here, we offer an extensive review of pyrrolo[2,1-f][1,2,4]triazin-4(1H)-one and pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one, describing their biological properties en route to drug discovery.

Antimycobacterial Activity, Synergism, and Mechanism of Action Evaluation of Novel Polycyclic Amines against Mycobacterium tuberculosis.

Mycobacterium tuberculosis has developed extensive resistance to numerous antimycobacterial agents used in the treatment of tuberculosis. Insufficient intracellular accumulation of active moieties allows for selective survival of mycobacteria with drug resistance mutations and accordingly promotes the development of microbial drug resistance. Discovery of compounds with new mechanisms of action and physicochemical properties that promote intracellular accumulation, or compounds that act synergistically with other antimycobacterial drugs, has the potential to reduce and prevent further drug resistance. To this end, antimycobacterial activity, mechanism of action, and synergism in combination therapy were investigated for a series of polycyclic amine derivatives. Compound selection was based on the presence of moieties with possible antimycobacterial activity, the inclusion of bulky lipophilic carriers to promote intracellular accumulation, and previously demonstrated bioactivity that potentially support inhibition of efflux pump activity. The most potent antimycobacterial demonstrated a minimum inhibitory concentration (MIC99) of 9.6 μM against Mycobacterium tuberculosis H37Rv. Genotoxicity and inhibition of the cytochrome bc1 respiratory complex were excluded as mechanisms of action for all compounds. Inhibition of cell wall synthesis was identified as a likely mechanism of action for the two most active compounds (14 and 15). Compounds 5 and 6 demonstrated synergistic activity with the known Rv1258c efflux pump substrate, spectinomycin, pointing to possible efflux pump inhibition. For this series, the nature of the side chain, rather than the type of polycyclic carrier, seems to play a determining role in the antimycobacterial activity and cytotoxicity of the compounds. Contrariwise, the nature of the polycyclic carrier, particularly the azapentacycloundecane cage, appears to promote synergistic activity. Results point to the possibility of combining an azapentacycloundecane carrier with a side chain that promotes antimycobacterial activity to develop dual acting molecules for the treatment of Mycobacterium tuberculosis.

Trends in NMR Structural Elucidation Of Polycyclic Cages, Namely: Adamantane, Pentacycloundecane and Trishomocubane

ABSTRACT Advances in Nuclear Magnetic Resonance (NMR) spectroscopy is a cornerstone in structure elucidation of polycyclic 'cage' scaffolds. Due to the compactness of these compounds, much overlap, as well as unique through-space and bond NMR interactions are frequently observed. This review serves as a guide for the NMR elucidation of future derivatives by providing some of the typical and relevant aspects of the characteristic trends, substituent patterns and chemical shift behaviour for the identification of the polycyclic structures, namely adamantane, pentacycloundecane and trishomocubane derivatives. Keywords: adamantane, NMR elucidation, pentacycloundecane, polycyclic compounds, trishomocubane

Natural polyenic macrolactams and polycyclic derivatives generated by transannular pericyclic reactions: optimized biogenesis challenging chemical synthesis.

Covering from 1992 to the end of 2020-11-20.Genetically-encoded polyenic macrolactams, which are constructed by Nature using hybrid polyketide synthase/nonribosomal peptide synthase (PKSs/NRPSs) assembly lines, are part of the large collection of natural products isolated from bacteria. Activation of cryptic (i.e., silent) gene clusters in these microorganisms has more recently allowed to generate and eventually isolate additional members of the family. Having two unsaturated fragments separated by short saturated chains, the primary macrolactam is posited to undergo transannular reactions and further rearrangements thus leading to the generation of a structurally diverse collection of polycyclic (natural) products and oxidized derivatives. The review will cover the challenges that scientists face on the isolation of these unstable compounds from the cultures of the producing microorganisms, their structural characterization, biological activities, optimized biogenetic routes, as well as the skeletal rearrangements of the primary structures of the natural macrolactams derived from pericyclic reactions of the polyenic fragments. The efforts of the synthetic chemists to emulate Nature on the successful generation and structural confirmation of these natural products will also be reported.

Synthesis of Polycyclic Furan and Chromene Derivatives via Cascade Reactions Enabled by Cleavage of Multiple C(sp3)−F Bonds

AbstractThe strong and unreactive C−F bond makes polyfluorocarbons extremely long‐lived and potentially toxic. A successive selective and controllable C(sp3)−F functionalization of polyfluoroalkylated ketones with S‐ and O‐nucleophiles to enable efficient synthesis of pharmaceutically important fluorine‐ and sulfur‐containing polycyclic furan and chromene derivatives under transition metal‐free conditions is demonstrated here. The combination of C−S/C−O coupling, aromatization, and cyclization cascade contribute to the accurate four/five C(sp3)−F bond cleavage at two different sites of perfluoroalkyl chain. The formation of reactive quinoid intermediates and the necessity of using TBAB (tetrabutylammonium bromide) as additive and Cs2CO3 as base were identified by detailed mechanistic studies.magnified image

Metal and Oxidant Free Construction of Substituted‐ and/or Polycyclic Indoles: A Useful Alternative to Bischler and Related Syntheses

A wide range of substituted indoles or polycyclic derivatives containing the indole core are easily accessible by acidic treatment of aromatic amines and 1,2‐diaza‐1,3‐dienes. Unlike the related indole‐Bischler synthesis, the regioselectivity of the method here reported is unique and predictable, the yields are generally good and also electron withdrawing substituted indoles are smoothly recovered.

Synthesis of Polycyclic Systems Based on Sulfolenes

The review analyzes and summarizes methods for the synthesis of polycyclic derivatives of sulfolane (sulfolene). The reactions of polyalkylation, transformations of functional groups of the sulfolene ring, as well as the addition reaction at endo- and exocyclic multiple bonds are considered.

New complex polycyclic compounds: Synthesis, antiproliferative activity and mechanism of action

Polycyclic or O-glycoconiugate polycyclic compounds 1a-g were previously tested for their in vitro antiproliferative activity. In this series of compounds, activity increases as log P decreases. Specifically, compounds 1d and 1g showed lower log P values together with the best antiproliferative profiles. With the aim of extending our understanding of the structure–activity relationship (SAR) of this class of compounds, we prepared new polycyclic derivatives 2a-c, which bear on each of the two phenyl rings hydrophilic substituents (OH, SO2NH2 or NHCOCH3). These substituents are able to form hydrogen bonds and to decrease the partition coefficient value as compared with compound 1d. Compound 2a was slightly more active than 1d, while 2b and 2c had antiproliferative activity comparable to that of 1d. Finally, the role of the two phenyl groups of polycycle derivatives 1 was also investigated. The analog 3, which bears two methyls instead of the two phenyls had a lower log P value (2.94 ± 1.22) than all the other compounds, but it had negligible antiproliferative activity at 10 µM. The analysis of the most active derivative 2a revealed a significant antiproliferative activity against the triple-negative breast cancer cell line MDA-MB231. After a 24 h treatment, an autophagic process was activated, as demonstrated by an increase in monodansylcadaverine-positive cells as well as by the appearance of the autophagic markers Beclin and LC3II. Prolonging the treatment to 48 h, 2a caused cytotoxicity through the activation of caspase-dependent apoptosis.

A simple and easy to perform synthetic route to functionalized thienyl bicyclo[3.2.1]octadienes.

In order to prepare novel polycyclic derivatives of bicyclo[3.2.1]octadiene systems fused with a thiophene ring, photochemical cyclization and aldol condensation reactions were carried out. The starting substrates were easily obtained by a Vilsmeier–Haack reaction of bicyclo[3.2.1]octadiene thiophene derivatives with dimethylformamide. From the obtained carbaldehydes, novel methyl, methoxy, and cyano-substituted styryl thienobenzobicyclo[3.2.1]octadiene derivatives were synthesized through Wittig reactions and subjected to photochemical cyclization, in terms of obtaining the new annulated structures. As part of this study, the aldol reaction of the starting 2-substituted carbaldehyde with acetone was also performed, which produced the thieno-fused benzobicyclo[3.2.1]octadiene compound with an extended conjugation.

Jatrophane and rearranged jatrophane-type diterpenes: biogenesis, structure, isolation, biological activity and SARs (1984-2019).

Diterpene compounds specially macrocyclic ones comprising jatrophane, lathyrane, terracinolide, ingenane, pepluane, paraliane, and segetane skeletons occurring in plants of the Euphorbiaceae family are of considerable interest in the context of natural product drug discovery programs. They possess diverse complex skeletons and a broad spectrum of therapeutically relevant biological activities including anti-inflammatory, anti-chikungunya virus, anti-HIV, cytotoxic, and multidrug resistance-reversing activities as well as curative effects on thrombotic diseases. Among macrocyclic diterpenes of Euphorbia, the discovery of jatrophane and modified jatrophane diterpenes with a wide range of structurally unique polyoxygenated polycyclic derivatives and as a new class of powerful inhibitors of P-glycoprotein has opened new frontiers for research studies on this genus. In this review, an attempt has been made to give in-depth coverage of the articles on the naturally occurring jatrophanes and rearranged jatrophane-type diterpenes isolated from species belonging to the Euphorbiaceae family published from 1984 to March 2019, with emphasis on the biogenesis, isolation methods, structure, biological activity, and structure–activity relationship. Electronic supplementary materialThe online version of this article (10.1007/s11101-020-09667-8) contains supplementary material, which is available to authorized users.

Hyperacmosins H-J, three new polycyclic polyprenylated acylphloroglucinol derivatives from Hypericum acmosepalum

Three new polycyclic polyprenylated acylphloroglucinol derivatives, hyperacmosins H-J (1–3), with four known compounds (4–7), were isolated from the air-dried aerial parts of Hypericum acmosepalum. Especially, compounds 1 and 2 were identified as methylated polycyclic polyprenylated acylphloroglucinol derivatives (mPPAPs). Their structures were established by NMR, HRESIMS and experimental electronic circular dichroism (ECD) spectra. The hepatoprotective activity of seven compounds were evaluated. Compounds 1 and 5 exhibited hepatoprotective activity against paracetamol-induced HepG2 cell damage.

1,3-Dipolar cycloaddition of N-allyl substituted polycyclic derivatives of isoindole-1,3-dione with nitrones and nitrile oxides: An experimental and theoretical investigation

Cycloaddition reactions of N-allyl substituted polycyclic derivatives of isoindole-1,3-dione with nitrones proceeds regio- and stereoselectively on the double bond of the N-allyl substituent giving substituted isoxazolidines with good yields. Regioselectivity of the cycloaddition of this dipolarophiles with nitrile oxides depends on the structure of unsaturated hydrocarbon scaffold and the reaction selectively leads to adducts on endocyclic or the double bond of the N-allyl substituent. DFT calculations were used to investigate the reasons of the selectivity.

Retracted: Design and synthesis of a bismethylsulfanyl‐steroid‐azetyl butanol derivative from 2‐nitroestradiol

AbstractSeveral studies for the synthesis of polycyclic derivatives have been reported; however, there is little information on the preparation of steroid‐polycyclic derivatives. In this way, the aim of this study was to synthesize a bismethylsulfanyl‐steroid‐azetyl butanol derivative (compound 10) from 2‐nitroestrone. The chemical structure was evaluated through both 1H NMR and 13C NMR or spectroscopic analysis. The results showed a good yielding from 10. It is noteworthy that the reagents used in this investigation are not expensive and do not require special conditions for handling.

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

Abstract2‐Indolylmethanols have been recently involved in several processes dealing with indole functionalization. These compounds, upon activation by Brønsted or Lewis acids, generate a bidentate electrophilic system amenable to react at the 3‐position or at the benzylic site with a wide range of nucleophilic reagents. The functionalization pattern is affected by the nature of the substituents at the carbinol unit and also depends on the nature of the nucleophile used. Nucleophilic reactants bearing a remote electrophilic site in their structure can be involved in a further ring closure ultimately leading to polycyclic derivatives. This review article summarizes some fundamental aspects of the chemistry of 2‐indolylmethanols with particular attention to those related to asymmetric synthesis.magnified image

Structure of an Unusual Tetracyclic Deoxyguanosine Adduct: Implications for Frameshift Mutagenicity of ortho-Cyano Nitroanilines.

Nitroaromatic compounds represent a major class of industrial chemicals that are also found in nature. Polycyclic derivatives are regarded as potent mutagens and carcinogens following bioactivation to produce nitrenium electrophiles that covalently modify DNA to afford N-linked C8-2'-deoxyguanosine (C8-dG) lesions that can induce frameshift mutations, especially in CpG repeat sequences. In contrast, their monocyclic counterparts typically exhibit weak mutagenicity or a lack thereof, despite also undergoing bioactivation to afford N-linked C8-dG adducts. Recently, it has been reported that cyano substitution can greatly increase the mutagenicity of nitroaniline derivatives that are components of azo dyes. The basis of this "cyano effect" may be rooted in the formation of a novel polycyclic adduct arising from initial formation of the N-linked C8-dG adduct followed by a cyclization process involving N7 of dG and the ortho-CN group of the attached C8-aryl moiety to generate a quinazolinimine ring as part of a fused tetracyclic C8,N7-dG adduct structure. The present work structurally characterizes this novel cyclic adduct using a combination of optical spectroscopies, NMR analysis, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. Our data indicate that this highly fluorescent cyclic adduct adopts the promutagenic syn conformation and can stabilize the slipped mutagenic intermediate (SMI) within the CpG repeat of the NarI sequence, which is a hotspot for frameshift mutagenesis mediated by polycyclic N-linked C8-dG adducts. In contrast, the open para-CN (4-aminobenzontrile-derived) N-linked C8-dG adduct is less likely to disrupt the canonical B-form. Together, our results provide a rationale for the potent mutagenicity of cyano-substituted nitroaniline derivatives recently reported in frameshift-sensitive tester strains.

Polycyclic polyprenylated acylphloroglucinol derivatives with neuroprotective effects from Hypericum monogynum

A new polycyclic polyprenylated acylphloroglucinol (PPAP), hypermonin C (1), along with nine known PPAPs (2–10) were obtained from the leaves and twigs of Hypericum monogynum. The structures of the isolates were determined on the basis of extensive spectroscopic analysis. The neuroprotective effects of the isolates against several chemical-induced injuries in SH-SY5Y and PC12 cells were assessed, and most of the compounds exhibited significant protective effects at 10 μg/ml. Especially, three compounds (1, 3, and 7) showed excellent neuroprotective activity with a cell viability of 92.4% ∼ 95.8% in KCl-induced SH-SY5Y cell injury. Their preliminary structure-activity relationship was also discussed and the configuration of substituent in furohyperforin may be critical for the neuroprotective activity of PPAP derivatives.

Quaternary Carbon Center Forming [3 + 2] Cyclization Reaction by Adjusting the Substituents of Substrates.

Herein, we describe a variety of chiral hybrid pyrroidine-indole polycyclic derivatives with quaternary and continuous chiral centers were synthesized in good yields with excellent stereoselectivities through an asymmetric, intermolecular, and formal [3 + 2] cyclization reaction catalyzed by a bifunctional catalyst. In addition, the selection of substituents of substrates is the key to success, and both the hydroxyl group and the trifluoromethyl group play essential roles in the reaction.

Acetyl- and butyrylcholinesterase inhibitory activity of selected photochemicallysynthesized polycycles

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the elderly population. Since the treatment of AD has been associated with the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), their inhibitors remain the main focus of AD investigations. In this study we evaluated cholinesterase inhibitory activity of 14 bicyclo[3.2.1]octene/octadiene derivatives and naturally occurring sesquiterpene alcohol cedrol. These 14 compounds have been efficiently and ecologically prepared by a photochemical approach in batch photochemical reactors. Various compounds with the bicyclo[3.2.1]octene skeleton have already been successfully evaluated for treatment of central nervous system disorders and AD. Among the tested polycyclic derivatives, compounds 4-[(9$S)$-tricyclo[6.3.1.0$^{2,7}$]dodeca-2,4,6,10-tetraen-9-yl]pyridine (\textbf{3}) and (11$S)$-11-(4-chlorophenyl)-12-[($E)$-2-(4-chlorophenyl)ethenyl]tricyclo[6.3.1.0$^{2,7}$]dodeca-2,4,6,9-tetraene (\textbf{6}) showed the best inhibitory activity on BChE (IC$_{50}$ = 8.8 $\mu $M) and AChE (IC$_{50}$ = 17.5 $\mu $M), respectively.

Copper-Catalyzed N-H/C-H Sequential Relay Oxidative Radical Carboannulation: Construction of Diversely Substituted [60]Fullerene-Fused Tetrahydrocyclopenta[b]indoles.

Reported herein is a new copper-catalyzed N-H/C-H sequential relay oxidative radical carboannulation of [60]fullerene with C2-functionalized free indoles for the direct construction of novel [60]fullerene-fused tetrahydrocyclopenta[b]indoles. The transformation shows high regioselectivity and atom economy, broad substrate scope, and good functional group tolerance, providing an efficient and practical approach to access diversely substituted fullerene-fused polycyclic derivatives from simple hydrocarbons.