Synthesis of hybrid molecules containing pyrimidine and diterpene alkaloid lappaconitine fragments

Черемных, Кирилл П.; Savel'ev, V. A.; Shkurko, O. P.; Шульц, Э. Э.

doi:10.1007/s10593-019-02404-w

Cited by 9 publications

(7 citation statements)

References 15 publications

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“…Previously, we successfully synthesized lappaconitine ynones 5, 6 by the employment of transition-metal-catalyzed cross-coupling reactions of 5 -ethynyllappaconitine 2 [39] with benzoic acid chlorides 3, 4 under Sonogashira cross-coupling reaction (Scheme 1) [38]. We observed that compounds 5 could be almost quantitatively converted into 2,4,6-trisubstituted pyrimidines 7, 8 by refluxing with acetamidine hydrochloride 9 or guanidine hydrocarbonate 10 in acetonitrile in the presence of Na 2 CO 3 (2 equivalent) with the isolated yield 81-95%.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…Exploiting pharmacophore hybridization and in the connection of optimization of the lappaconitine structure (for reducing the toxicity and improving the analgesic activity), we combined the two pharmacophoric units in a single entity. In the framework of our studies dealing with the development of the synthesis of pyrimidinyl-lappaconitine hybrid compounds [38], we report herein the convenient multi component strategy route to those compounds from lappaconitine 1. The antinociceptive activity of new compounds was also investigated and discussed.…”

Section: Introductionmentioning

confidence: 99%

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Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

et al. 2020

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Convenient and efficient routes to construct hybrid molecules containing diterpene alkaloid lappaconitine and pyrimidine fragments are reported. One route takes place via first converting of lappaconitine to 1-ethynyl-lappaconitine, followed by the Sonogashira cross-coupling-cyclocondensation sequences. The other involves the palladium-catalyzed carbonylative Sonogashira reaction of 5′-iodolappaconitine with aryl acetylene and Mo (CO)6 as the CO source in acetonitrile and subsequent cyclocondensation reaction of the generated alkynone with amidines. The reaction proceeded cleanly in the presence of the PdCl2-(1-Ad)2PBn∙HBr catalytic system. The protocol provides mild reaction conditions, high yields, and high atom and step-economy. Pharmacological screening of lappaconitine-pyrimidine hybrids for antinociceptive activity in vivo revealed that these compounds possessed high activity in experimental pain models, which was dependent on the nature of the substituent in the 2 and 6 positions of the pyrimidine nucleus. Docking studies were undertaken to gain insight into the possible binding mode of these compounds with the voltage-gated sodium channel 1.7. The moderate toxicity of the leading compound 12 (50% lethal dose (LD50) value was more than 600 mg/kg in vivo) and cytotoxicity to cancer cell lines in vitro encouraged the further design of therapeutically relevant analogues based on this novel type of lappaconitine–pyrimidine hybrids.

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Section: Chemical Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

et al. 2020

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“…More recently, Mandal and co-workers reported the synthesis of 4-substituted pyrimidin-2-amines through a copper-free acyl Sonogashira step of (hetero)aryl, tert-butyl and adamantyl acid chlorides with trimethylsilylacetylene, performed using palladium(0) NPs anchored onto single walled carbon nanotubes (SWNT-PdNPs) as their catalyst, followed by treatment with guanidine hydrochloride in the presence of Na2CO3 as the base; in all cases, N-heterocycles were obtained in satisfactory yields (Scheme 35) [55,56]. In 2018, Shults et al [28] proposed instead the synthesis of diterpene alkaloid lappaconitine derivatives with pyrimidine rings by one-pot acyl Sonogashira/guanidinium Michael addition/cyclocondensation. The applicability of the present protocol was also tested on the synthesis of a dipyrimidyl pyridine (DIPYRIMPY) derivative starting from pyridine-2,6-dicarbonyl dichloride [24,81].…”

Section: Scheme 24mentioning

confidence: 99%

“…More recently, Mandal and co-workers reported the synthesis of 4-substituted pyrimidin-2-amines through a copper-free acyl Sonogashira step of (hetero)aryl, tert-butyl and adamantyl acid chlorides with trimethylsilylacetylene, performed using palladium(0) NPs anchored onto single walled carbon nanotubes (SWNT-PdNPs) as their catalyst, followed by treatment with guanidine hydrochloride in the presence of Na2CO3 as the base; in all cases, N-heterocycles were obtained in satisfactory yields (Scheme 35) [55,56]. In 2018, Shults et al [28] proposed instead the synthesis of diterpene alkaloid lappaconitine derivatives with pyrimidine rings by one-pot acyl Sonogashira/guanidinium Michael addition/cyclocondensation. More recently, Mandal and co-workers reported the synthesis of 4-substituted pyrimidin-2-amines through a copper-free acyl Sonogashira step of (hetero)aryl, tert-butyl and adamantyl acid chlorides with trimethylsilylacetylene, performed using palladium(0) NPs anchored onto single walled carbon nanotubes (SWNT-PdNPs) as their catalyst, followed by treatment with guanidine hydrochloride in the presence of Na 2 CO 3 as the base; in all cases, N-heterocycles were obtained in satisfactory yields (Scheme 35) [55,56].…”

Section: Scheme 24mentioning

confidence: 99%

Acyl Sonogashira Cross-Coupling: State of the Art and Application to the Synthesis of Heterocyclic Compounds

Albano

Aronica

2019

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The acyl Sonogashira reaction represents an extension of Sonogashira cross-coupling to acid chlorides which replace aryl or vinyl halides, while terminal acetylenes are used as coupling partners in both reactions. The introduction of a carbonyl functional group on the alkyne backbone determines a radical change in the reactivity of the products. Indeed, α,β-alkynyl ketones can be easily converted into different heterocyclic compounds depending on the experimental conditions employed. Due to its potential, the acyl Sonogashira reaction has been deeply studied with particular attention to the nature of the catalysts and to the structures of both coupling compounds. Considering these two aspects, in this review, a detailed analysis of the literature data regarding the acyl Sonogashira reaction and its role in the synthesis of several heterocyclic derivatives is reported.

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“…In the framework of our studies dealing with the development of convenient routes to functionalization of some plant metabolites or their derivatives [41][42][43][44], we report herein the synthesis of a range of 1-hydroxy substituted anthraquinones containing an aryl substituent in the 2 or 4 (or 2 and 4 simultaneously) position of the anthraquinone core. As a starting compound, we used the 1-hydroxy-4-iodoanthraquinone (1), 1-hydroxy-2-bromoanthraquinone (2) or 1-hydroxy-2,4-dibromoanthraquinones (3) which were obtained from 1-hydroxy-9,10-anthraquinone or 4-amino-1-hydroxy-9,10-anthraquinone by the known procedures [45,46].…”

Section: Introductionmentioning

confidence: 99%

1-Hydroxyanthraquinones Containing Aryl Substituents as Potent and Selective Anticancer Agents

et al. 2020

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A series of 1,2-, 1,4-disubstituted or 1,2,4-trisubstituted anthraquinone-based compounds was designed, synthesized, characterized and biologically evaluated for anticancer efficacy. 2- or 4-arylated 1-hydroxy-9,10-antraquinones (anthracene-9,10-diones) were prepared by Suzuki–Miyaura cross-coupling reaction of 1-hydroxy-2-bromoanthraquinone, 1-hydroxy-4-iodoanthraquinone or 1-hydroxy-2,4-dibromoanthraquinone with arylboronic acids. The cross-coupling reaction of 2,4-dibromo-9,10-anthraquinone with arylboronic acids provide a convenient approach to 2,4-bis arylated 1-hydroxyanthraquinones with a variety of aryl substituent in the 2 and 4 position. The cytotoxicity of new anthraquinone derivatives was evaluated using the conventional MTT assays. The data revealed that six of the aryl substituted compounds among the entire series 3, 15, 16, 25, 27, 28 were comparable potent with the commercially available reference drug doxorubicin on the human glioblastoma cells SNB-19, prostate cancer DU-145 or breast cancer cells MDA-MB-231 and were relatively safe towards human telomerase (h-TERT)immortalized lung fibroblasts cells. The results suggested that the in vitro antitumor activity of synthesized 2-aryl, 4-aryl- and 2,4-diaryl substituted 1-hydroxyanthraquinones depends on the nature of the substituent within the cyclic backbone. Docking interaction of 2-, 4-substituted and 2,4-disubstituted 1-hydroxyanthraquinones indicates intercalative mode of binding of compounds with DNA topoisomerase. The interaction with the DNA of 4-aryl-13, 15, 16 and 4-(furan-3-yl)-23 1-hydroxyanthraquinones was experimentally confirmed through a change in electroforetic mobility. Further experiments with 1-hydroxy-4-phenyl-anthraquinone 13 demonstrated that the compound induced cell cycle arrest at sub-G1 phase in DU-145 cells in the concentration 1.1 μM, which is probably achieved by inducing apoptosis. 4-Arylsubstituted 1-hydroxyanthraquinones 13 and 16 induced the enhancement of DNA synthesis on SNB19 cell lines.

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Synthesis of hybrid molecules containing pyrimidine and diterpene alkaloid lappaconitine fragments

Cited by 9 publications

References 15 publications

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

Acyl Sonogashira Cross-Coupling: State of the Art and Application to the Synthesis of Heterocyclic Compounds

1-Hydroxyanthraquinones Containing Aryl Substituents as Potent and Selective Anticancer Agents

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