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1.
Org Biomol Chem ; 2024 Sep 09.
Article in English | MEDLINE | ID: mdl-39247987

ABSTRACT

Three short and efficient total syntheses of cassiarin C are reported, from a chromanone common key intermediate. A C-H activation strategy, under rhodium catalysis on its pivaloyl oxime, enabled the installation of the pyridine ring. Dehydrogenation of 8-O-methylcassiarin C afforded 8-O-methylcassiarin A. A kinetic experiment and DFT calculations of the intermediates helped to gain insight into the unusual site- and stereo-specific H/D exchange of cassiarin C in CD3OD.

2.
ChemistryOpen ; 13(5): e202300306, 2024 May.
Article in English | MEDLINE | ID: mdl-38647363

ABSTRACT

Multicomponent reactions (MCRs) offer a highly useful and valuable strategy that can fulfill an important role in synthesizing complex polysubstituted compounds, by simplifying otherwise long sequences and increasing their efficiency. The total synthesis of selected natural products employing three-component reactions as their common strategic MCR approach, is reviewed on a case-by-case basis with selected targets conquered during the last 15 years. The revision includes detailed descriptions of the selected successful sequences; relevant information on the isolation, and bioactivity of the different natural targets is also briefly provided.

3.
Org Biomol Chem ; 22(3): 429-465, 2024 Jan 17.
Article in English | MEDLINE | ID: mdl-38126459

ABSTRACT

The total syntheses of selected natural products using different versions of the Ugi multicomponent reaction is reviewed on a case-by-case basis. The revision covers the period 2008-2023 and includes detailed descriptions of the synthetic sequences, the use of state-of-the-art chemical reagents and strategies, as well as the advantages and limitations of the transformation and some remedial solutions. Relevant data on the isolation and bioactivity of the different natural targets are also briefly provided. The examples clearly evidence the strategic importance of this transformation and its key role in the modern natural products synthetic chemistry toolbox. This methodology proved to be a valuable means for easily building molecular complexity and efficiently delivering step-economic syntheses even of intricate structures, with a promising future.

4.
ACS Omega ; 8(25): 23174-23181, 2023 Jun 27.
Article in English | MEDLINE | ID: mdl-37396254

ABSTRACT

An efficient and straightforward route toward the isatin-type natural product melosatin A is reported, employing a trisubstituted aniline as a key intermediate. The latter was synthesized in 4 steps and 60% overall yield from eugenol, through its regioselective nitration, sequentially followed by a Williamson methylation, an olefin cross-metathesis with 4-phenyl-1-butene and the simultaneous reduction of olefin and nitro groups. The final step, a Martinet cyclocondensation of the key aniline with diethyl 2-ketomalonate, provided the natural product with 68% yield.

5.
RSC Adv ; 13(20): 13715-13724, 2023 May 02.
Article in English | MEDLINE | ID: mdl-37152581

ABSTRACT

Two total syntheses of quindoline, which take place through the intermediacy of 3-nitroquinoline derivatives, are reported. The general synthetic sequence involves construction of the latter by mechanochemical condensation of benzaldehydes with 2-amino-nitrostyrene, followed either by reduction of the nitro group of the heterocycle and Buchwald-Hartwig cyclization or by a nitrene-mediated cyclization under solventless conditions. Use of PPh3 to generate the nitrene resulted in the unprecedented formation of a phosphazene in place of quindoline. This unexpected transformation was explained by means of DFT computations.

6.
J Org Chem ; 87(20): 13494-13500, 2022 10 21.
Article in English | MEDLINE | ID: mdl-35324169

ABSTRACT

The first total synthesis of the marine alkaloid aqabamycin G is disclosed. The synthetic sequence involved the stepwise addition to maleimide of an indole motif and a substituted diazo-benzenoid unit derived from acetaminophen. An alternative strategy using a protected phenol is also reported.


Subject(s)
Alkaloids , Antineoplastic Agents , Vibrio , Acetaminophen , Maleimides , Indoles , Phenols , Indole Alkaloids
7.
Molecules ; 27(2)2022 Jan 09.
Article in English | MEDLINE | ID: mdl-35056725

ABSTRACT

In the context of our SAR study concerning 6BrCaQ analogues as C-terminal Hsp90 inhibitors, we designed and synthesized a novel series of 3-(heteroaryl)quinolin-2(1H), of types 3, 4, and 5, as a novel class of analogues. A Pd-catalyzed Liebeskind-Srogl cross-coupling was developed as a convenient approach for easy access to complex purine architectures. This series of analogues showed a promising biological effect against MDA-MB231 and PC-3 cancer cell lines. This study led to the identification of the best compounds, 3b (IC50 = 28 µM) and 4e, which induce a significant decrease of CDK-1 client protein and stabilize the levels of Hsp90 and Hsp70 without triggering the HSR response.


Subject(s)
HSP90 Heat-Shock Proteins
8.
ACS Omega ; 6(30): 19356-19363, 2021 Aug 03.
Article in English | MEDLINE | ID: mdl-34368522

ABSTRACT

The broad-spectrum antiviral Remdesivir, a monophosphate nucleoside analogue prodrug (ProTide), was repurposed. In May 2020, it received emergency approval by the FDA, being the first drug approved to fight the new coronavirus (COVID-19) disease which targets the virus directly. The main synthetic strategies toward Remdesivir, and their relevant modifications, are presented and discussed, to provide a panoramic view of the state-of-the-art and the more important advances in this field. Recent progress, proposed improvements, and uses of novel technologies for the synthetic sequence are also detailed.

9.
Heliyon ; 7(3): e06436, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33763610

ABSTRACT

Langmuir and Langmuir-Blodgett films holding a synthetic bioinspired wound healing active compound were used as drug-delivery platforms. Palmitic acid Langmuir monolayers were able to incorporate 2-methyltriclisine, a synthetic Triclisine derivative that showed wound healing activity. The layers proved to be stable and the nanocomposites were transferred to solid substrates. Normal human lung cells (Medical Research Council cell strain 5, MRC-5) were grown over the monomolecular Langmuir-Blodgett films that acted as a drug reservoir and delivery system. The proliferation and migration of the cells were clearly affected by the presence of 2-methyltriclisine in the amphiphilic layers. The methodology is proposed as a simple and reliable model for the study of the effects of bioactive compounds over cellular cultures.

10.
RSC Adv ; 10(32): 18978-19002, 2020 May 14.
Article in English | MEDLINE | ID: mdl-35518305

ABSTRACT

Cryptosanguinolentine (isocryptolepine) is one of the minor naturally-occurring monomeric indoloquinoline alkaloids, isolated from the West African climbing shrub Cryptolepis sanguinolenta. The natural product displays such a simple and unique skeleton, which chemists became interested in well before it was found in Nature. Because of its structure and biological activity, the natural product has been targeted for synthesis on numerous occasions, employing a wide range of different strategies. Hence, discussed here are aspects related to the isolation of isocryptolepine, as well as the various approaches toward its total synthesis.

11.
RSC Adv ; 9(57): 33096-33106, 2019 Oct 15.
Article in English | MEDLINE | ID: mdl-35529133

ABSTRACT

A straightforward and convenient approach toward the first total synthesis of ampullosine, a structurally unique 3-methylisoquinoline alkaloid isolated from Sepedonium ampullosporum, is reported. Access to the related O-methyl ampullosine methyl ester from a common intermediate is also disclosed. The synthetic sequence toward the natural product comprised a Kolbe-type carboxylation of 3,5-dihydroxybenzoic acid and further esterification of the diacid, followed by masking of one of the phenols through selective ester reduction and subsequent acetonide formation. Installation of the three-carbon atom required for the 3-methylpyridine ring was performed by triflation of the remaining free phenol and a Pd-catalyzed Suzuki-Miyaura reaction with potassium E-propenyltrifluoroborate. Deprotection of the acetonide, followed by partial oxidation of the benzylic alcohol to the salicylaldehyde, O-methylation of the free phenol and hydrazonation of the resulting ortho-anisaldehyde derivative gave a hydrazone-based 1-azatriene. This was further subjected to 6π-azaelectrocyclization to afford permethylampullosine (11 steps, 14% overall yield), whereas exhaustive demethylation with AlI3 generated in situ gave ampullosine (12 steps, 3.2% global yield).

12.
Nat Prod Rep ; 36(2): 354-401, 2019 02 20.
Article in English | MEDLINE | ID: mdl-30090891

ABSTRACT

Covering: 2006 to 2018 The application of the 6π-azaelectrocyclization of azatrienes as a key strategy for the synthesis of natural products, their analogs and related bioactive or biomedically-relevant compounds (from 2006 to date) is comprehensively reviewed. Details about reaction optimization studies, relevant reaction mechanisms and conditions are also discussed.


Subject(s)
Alkaloids/chemical synthesis , Biological Products/chemical synthesis , Chemistry Techniques, Synthetic/methods , Aza Compounds/chemistry , Cyclization , Histamine Agonists/chemical synthesis , Piperidines/chemistry , Pyridines/chemistry , Pyrroles/chemical synthesis , Quinazolines/chemical synthesis , Quinolizines/chemistry , Sesquiterpenes/chemical synthesis
13.
Org Lett ; 20(16): 5058-5061, 2018 08 17.
Article in English | MEDLINE | ID: mdl-30079739

ABSTRACT

Waltherione F was totally synthesized in seven steps and 31% overall yield from 2-nitro-3-methylanisole without the use of protecting groups. Key steps in the sequence were a Suzuki-Miyaura coupling to attach the n-octyl chain and a microwave-promoted cyclization of an acetonyl anthranilate to give the heterocyclic core whose 3-OH was O-methylated.

14.
Photochem Photobiol ; 94(5): 881-889, 2018 09.
Article in English | MEDLINE | ID: mdl-29729023

ABSTRACT

Pterin derivatives are heterocyclic compounds which are present in different biological systems. Neutral aqueous solutions of pterins present acid-base and keto-enol equilibria. These compounds, under UV-A radiation fluoresce, undergo photooxidation, generate reactive oxygen species and photoinduce the oxidation of biological substrates. As photosensitizers, they may act through different mechanisms, mainly through an electron transfer-initiated process (type-I mechanism), but they also produce singlet molecular oxygen (1 O2 ) upon irradiation (type-II mechanism). In general, upon UV-A excitation two triplet states, corresponding to the lactim and lactam tautomers, are formed, but only the last one is the responsible for the photosensitized reactions of biomolecules. We present a study of the photochemical properties of 3-methylpterin (3-Mep) which, in contrast to most pterin derivatives, exists only in the lactam form. Also an improvement in the synthesis of 3-Mep is reported. The spectroscopic properties 3-Mep in aqueous solution were similar to those of the unsubstituted pterin derivative (Ptr) in its acid form, such as absorption, fluorescent and phosphorescent emission spectra. Experiments using 2'-deoxyguanosine 5'-monophosphate (dGMP) as oxidizable target demonstrated that methylation at C-3 position of the pterin moiety does not affect significantly the efficiency of photosensitization, but results in a more photostable sensitizer.

15.
Nat Prod Rep ; 33(12): 1425-1446, 2016 Nov 23.
Article in English | MEDLINE | ID: mdl-27714041

ABSTRACT

Covering: up to April 2016Aspergillus and Penicillium are fungal species known to produce a high diversity of secondary metabolites, many of them endowed with interesting bioactivity. The small but steadily growing family of the naturally occurring 5-hydroxy-4-aryl-quinolin-2(1H)-one alkaloids and closely related compounds, which represent the results of various research projects that spanned over 20 years and involved scientists from different continents, are covered here. Emphasis is placed on the isolation and chemical structures of the different compounds, together with their source microorganisms, environmental conditions, country or region of origin, and relevant biological activities. In addition, stereochemical aspects, as well as the proposed biosynthetic pathways for the different members, and the incipient synthetic efforts towards some of the compounds or their key intermediates, are discussed in detail.


Subject(s)
Alkaloids , Aspergillus/chemistry , Biological Products , Penicillium/chemistry , Alkaloids/chemistry , Biological Products/chemistry , Biological Products/isolation & purification , Biological Products/pharmacology , Fungi/chemistry , Molecular Structure
17.
Org Biomol Chem ; 14(9): 2625-36, 2016 Mar 07.
Article in English | MEDLINE | ID: mdl-26906496

ABSTRACT

5-Hydroxy-4-aryl-3,4-dihydro-1H-quinolin-2-ones are a small family of natural products isolated from fungal strains of Penicillium and Aspergillus. Most of its members, which are insecticides and anthelmintics, carry an isoprenoid C-6 side chain. The synthesis of a 6-propenyl-substituted advanced intermediate for the total synthesis of these natural products is presented in this paper. This was achieved through the stereoselective construction of a ß,ß-diarylacrylate derivative from 6-nitrosalicylaldehyde, using a Wittig olefination and a Heck-Matsuda arylation, followed by a selective Fe(0)-mediated reductive cyclization. Installation of the 6-propenyl side chain was performed by 5-O-allylation of the heterocycle, followed by Claisen rearrangement and conjugative migration of the allyl double bond, as the key steps. The Grubbs II-catalyzed olefin cross metathesis of the 6-allyl moiety with 2-methylbut-2-ene to afford a precursor of peniprequinolone is also reported.


Subject(s)
Aspergillus/chemistry , Biological Products/chemical synthesis , Penicillium/chemistry , Quinolones/chemical synthesis , Biological Products/chemistry , Molecular Structure , Quinolones/chemistry
18.
Curr Top Med Chem ; 15(17): 1683-707, 2015.
Article in English | MEDLINE | ID: mdl-25915612

ABSTRACT

Plants are one of the most important resources for the discovery of new drugs. The potential of natural compounds as new drug leads is clearly illustrated by the discovery and development of many modern medicines. This is an encouraging factor that drives natural products research in the vegetable kingdom. Neocryptolepine is a tetracyclic nitrogen heterocycle isolated from the African climber Cryptolepis sanguinolenta, which is widely used in traditional African medicine in many countries of Central and West Africa. The natural product is one of the representative examples of the small family of indolo[2,3-b]quinoline alkaloids, being endowed of multiple biological activities, including DNA-binding and inhibition of the enzyme topoisomerase II. It is also cytotoxic, antibacterial, antifungal and molluscicidal, also displaying antiprotozoal activity, particularly as antitrypanosomal, antileishmanial, antischistosomal and antiplasmodial. Some of these activities have been related to the product's ability to bind to DNA and to inhibit topoisomerase II; however, the exact mechanisms behind all of the observed bioactivities have not been comprehensively clarified. Major research activities regarding neocryptolepine have been focused into two seemingly opposite fields, related to its cytotoxic and antimalarial properties. Optimization of the natural product as a cytotoxic agent implied improvements in its bioavailability and activity, while the need of non-cytotoxic compounds guided the design and optimization of antimalarial agents. Therefore, the aim of the present article is to systematically review the current knowledge about the diversity of the biological activities related to neocryptolepine, its analogs and derivatives.


Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Molluscacides/chemistry , Molluscacides/pharmacology
19.
Eur J Med Chem ; 81: 253-66, 2014 Jun 23.
Article in English | MEDLINE | ID: mdl-24852274

ABSTRACT

A novel series of symmetrically substituted 3,3-dibenzyl-4-hydroxy-3,4-dihydro-1H-quinolin-2-ones was synthesized and tested as antimicrobials. The minimum inhibitory concentration (MIC) values of the most active heterocycles were slightly higher than those exhibited by levofloxacin, employed as comparator. Structural factors affecting the activity were explored along three diversification points, including the substituents of the aromatic rings of the 3-benzyl moieties, as well as the functionalization of both, the homocyclic ring of the heterocycle and the quinolonic nitrogen atom. 6-Chloro and 3,3-bis(4'-chlorobenzyl) derivatives showed the lower MIC values. Optimally substituted heterocycles were synthesized, which exhibited enhanced activity.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Quinolines/chemistry , Quinolones/chemistry , Quinolones/pharmacology , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Gram-Negative Bacteria/cytology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/cytology , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
20.
Org Biomol Chem ; 12(22): 3735-43, 2014 Jun 14.
Article in English | MEDLINE | ID: mdl-24781876

ABSTRACT

An efficient one-pot synthetic approach towards ß-methylstyrenes is reported. The transformation, based on sequential homobimetallic catalysis, involves a Stille cross-coupling reaction between aryl halides and allyltributylstannane, followed by an in situ palladium-catalyzed conjugative isomerization. The reaction was optimized, and the best results were obtained with 10 mol% Pd(PPh3)2Cl2, 8.0 equiv. LiCl, and 0.5 equiv. PPh3 in diglyme at 130 °C for 12 h. It was demonstrated that the reaction tolerates a wide variety of functional groups.


Subject(s)
Chemistry, Organic/methods , Metals/chemistry , Styrenes/chemical synthesis , Catalysis , Stereoisomerism , Styrenes/chemistry
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