Synthesis Routes Towards the Farnesyl Protein Transferase Inhibitor ZARNESTRA<sup>TM</sup>

Angibaud, Patrick; Venet, Marc; Filliers, Walter; Broeckx, Rudy; Ligny, Yannick; Müller, Philippe; Poncelet, Virginie; End, David W.

doi:10.1002/ejoc.200300538

Cited by 117 publications

(45 citation statements)

References 17 publications

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“…Furthermore, the tetrazolyl compound 102 was observed to synergistically improve the efficiency of anti-tumor treatment when combined with conventional cytotoxic agents [129]. Recently, a 6-functionalised 1-aza coumarin 103 is undergoing human clinical trials as an orally active antitumor drug in view of its farnesyl protein-inhibiting activity in the nanomolar range [130].…”

mentioning

confidence: 99%

Recent Advances in Coumarins and 1-Azacoumarins as Versatile Biodynamic Agents

Kulkarni¹,

Kulkarni²,

Chao³

et al. 2006

CMC

225

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Coumarins, also referred as benzopyran-2-ones, and their corresponding nitrogen counterpart, 1-azacoumarins also referred to as carbostyrils, are a family of nature-occurring lactones and lactams respectively. The plant extracts containing coumarin-related heterocycles, which were employed as herbal remedies in early days, have now been extensively studied for their biological activities. These investigations have revealed their potentials as versatile biodynamic agents. For example, coumarins with phenolic hydroxyl groups have the ability to scavenge reactive oxygen species and thus prevent the formation of 5-HETE and HHT in the arachidonic pathway of inflammation suppression. Recent in vivo studies have revealed the role of coumarins in hepatotoxicity and also in depletion of cytochrome P450. Similarly 1-azacoumarins which is part of quinoline alkaloids, are known for their diverse biological activity and recently, a 6-functionalized 1-aza coumarins are undergoing human clinical trials as an orally active anti-tumor drug in view of its farnesyl protein-inhibiting activity in the nanomolar range. Furthermore, several synthetic coumarins with a variety of pharmacophoric groups at C-3, C-4 and C-7 positions have been intensively screened for anti-microbial, anti-HIV, anti-cancer, lipid-lowering, anti-oxidant, and anti-coagulation activities. Specifically, coumarin-3-sulfonamides and carboxamides were reported to exhibit selective cytotoxicity against mammalian cancer cell lines. The C4-substituted aryloxymethyl, arylaminomethyl, and dichloroacetamidomethyl coumarins, along with the corresponding 1-azacoumarins, have been demonstrated to be potential anti-microbial and anti-inflammatory agents. To expand the structural diversity of synthetic courmarins for biological functions, attempts have also been made to attach a chloramphenicol side chain at C-3 position of courmarin. In addition, the bi- and tri-heterocyclic coumarins and 1-azacoumarins with benzofuran, furan and thiazole ring systems along with biocompatible fragments like vanillin have shown remarkable potency as anti-inflammatory agents in animal models. Photobiological studies on pyridine-fused polycyclic coumarins have highlighted their potential as thymine dimer photosensitisers and the structurally related compounds of both coumarin and carbostyrils have also been found to act via the DNA gyrase pathway in their anti-bacterial activity. Apart from the above works, the present review also addresses the potential roles of coumarins and carbostyrils as protease inhibitors, or fluorescent probes in mechanistic investigation of biochemical pathways, and their application for QSAR in theoretical studies. Though 1-Azacoumarins have received less attention as compared to coumarins in the literature, an attempt has been made to compare both the systems at various stages, so that it can spark new thoughts on synthetic methodologies, reactivity pattern and biological activities.

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mentioning

confidence: 99%

Recent Advances in Coumarins and 1-Azacoumarins as Versatile Biodynamic Agents

Kulkarni¹,

Kulkarni²,

Chao³

et al. 2006

CMC

225

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“…Yu and coworkers succeded in obtaining the first example of lactamization of 2-alkenylanilines (158) with CO 2 to form 2-quinolinone derivatives (159) in high yields (26 examples, 42-95% yields) under atmospheric pressure (Scheme 68a) [145]. The 2-quinolinone motif is widely exploited in synthetic medicinal chemistry and photoelectric materials [146][147][148] and was previously accessed by the groups of Alper [149], Zhu [150] and Chuang [151] via lactamization of alkenyl and aryl C-H bonds with CO. Yu implemented, thus, a lactonization reaction using CO 2 founding that 2-alkenylanilines with R 2 = CH 3 (Scheme 68a) are more reactive than substrates with R 2 = H, Et. In contrast, both electron-donating and electron withdrawing substituents on the aniline nucleus do not affect significantly the substrate reactivity.…”

Section: Base-promoted Carboxylation Of Aromatic and Heteroaromatic Cmentioning

confidence: 99%

Direct Carboxylation of C(sp3)-H and C(sp2)-H Bonds with CO2 by Transition-Metal-Catalyzed and Base-Mediated Reactions

Tommasi

2017

Catalysts

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This review focuses on recent advances in the field of direct carboxylation reactions of C(sp 3 )-H and C(sp 2 )-H bonds using CO 2 encompassing both transition-metal-catalysis and base-mediated approach. The review is not intended to be comprehensive, but aims to analyze representative examples from the literature, including transition-metal catalyzed carboxylation of benzylic and allylic C(sp 3 )-H functionalities using CO 2 which is at a "nascent stage". Examples of light-driven carboxylation reactions of unactivated C(sp 3 )-H bonds are also considered. Concerning C(sp 3 )-H and C(sp 2 )-H deprotonation reactions mediated by bases with subsequent carboxylation of the carbon nucleophile, few examples of catalytic processes are reported in the literature. In spite of this, several examples of base-promoted reactions integrating "base recycling" or "base regeneration (through electrosynthesis)" steps have been reported. Representative examples of synthetically efficient, base-promoted processes are included in the review.

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“…Oxidative Heck reaction with 161 and cyclization/deacetylation then occurred to afford quinolinone 163 in 95% yield in one pot. This quinolinone was then converted to tipifarnib by the reported procedure [72]. In 2009, the synthesis of a sodium channel inhibitor was accomplished by Fagnou and coworkers by employing a palladium-catalyzed C-H arylation of an azine Noxide with a haloarene as the key reaction (Scheme 16.37) [48].…”

Section: Tipifarnib (C-h Alkenylation and Cyclization)mentioning

confidence: 99%

Synthesis of Natural Products and Pharmaceuticals via Catalytic CH Functionalization

Yamaguchi¹,

Amaike²,

Itami³

2016

Transition Metal‐Catalyzed Heterocycle Synthesis via CH Activation

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Synthesis Routes Towards the Farnesyl Protein Transferase Inhibitor ZARNESTRA^TM

Cited by 117 publications

References 17 publications

Recent Advances in Coumarins and 1-Azacoumarins as Versatile Biodynamic Agents

Recent Advances in Coumarins and 1-Azacoumarins as Versatile Biodynamic Agents

Direct Carboxylation of C(sp3)-H and C(sp2)-H Bonds with CO2 by Transition-Metal-Catalyzed and Base-Mediated Reactions

Synthesis of Natural Products and Pharmaceuticals via Catalytic CH Functionalization

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Synthesis Routes Towards the Farnesyl Protein Transferase Inhibitor ZARNESTRATM

Cited by 117 publications

References 17 publications

Recent Advances in Coumarins and 1-Azacoumarins as Versatile Biodynamic Agents

Recent Advances in Coumarins and 1-Azacoumarins as Versatile Biodynamic Agents

Direct Carboxylation of C(sp3)-H and C(sp2)-H Bonds with CO2 by Transition-Metal-Catalyzed and Base-Mediated Reactions

Synthesis of Natural Products and Pharmaceuticals via Catalytic CH Functionalization

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Product

Resources

About

Synthesis Routes Towards the Farnesyl Protein Transferase Inhibitor ZARNESTRA^TM