Synthesis of 2,4-diaza-4-deoxypodophyllotoxin, a new analogue of podophyllotoxin possessing antitumour activity

Hitotsuyanagi, Yukio; Naka, Yoichi; Yamagami, Keiji; Fujii, Akihiro; Tahara, Tetsuya

doi:10.1039/c39950000049

Cited by 20 publications

(10 citation statements)

References 15 publications

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“…Podophyllotoxin is known to bind to tubulin to a specific binding site different from those of vinblastine and paclitaxel . Synthesis of podophyllotoxin analogues have attracted much attention to reduce toxicity and improve antitumor activity . Hitotsuyanagi and collaborators synthesized (−)‐4‐aza‐4‐deoxypodophyllotoxin ( 45 ) from (−)‐podophyllotoxin ( 42 ) through C‐ring cleavage, Curtius rearrangement and intramolecular N‐alkylation as the key steps.…”

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

“…[37] Synthesis of podophyllotoxin analogues have attractedm uch attention to reduce toxicitya nd improvea ntitumor activity. [38,39] Hitotsuyanagi and collaboratorss ynthesized (À)-4-aza-4-deoxypodophyllotoxin (45)f rom (À)-podophyllotoxin (42) through C-ring cleavage, Curtius rearrangement and intramo-lecular N-alkylation as the key steps. Podophyllotoxin (42)w as converted to carboxylica cid 43 in eight steps.…”

Section: Tubulin Binding Agentsmentioning

confidence: 99%

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The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.

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Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

Section: Tubulin Binding Agentsmentioning

confidence: 99%

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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“…[74] The replacement of both the C2 and the C4 carbons by nitrogen results in active compounds with increased stereochemical stability and in vivo activity when compared with podophyllotoxin (4). [75] The development of synthetic methodologies towards 4-aza-2,3didehydropodophyllotoxin (26,28) analogues, such as the one-step multicomponent reactions of anilines or heterocyclic amines with tetronic acid or related reagents and aldehydes, has enabled fast access to podophyllotoxin-mimetic compounds. [76][77][78] The benzo or heteroaryl fused dihydropyridine scaffold preserves the active conformation of podophyllotoxin, (4) but with less troublesome stereochemical centers.…”

Section: Podophyllotoxin Derivativesmentioning

confidence: 99%

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Álvarez¹,

Aramburu²,

Puebla³

et al. 2016

CMC

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Antimitotics binding at the colchicine site of tubulin are important antitumour and vascular disrupting agents. Pyridines and azines are privileged scaffolds in medicinal chemistry and in recent years many colchicine site ligands (CSL) have incorporated them into their structures with the aim of improving their pharmacokinetic and pharmacodynamics properties. CSL have been classified according to their chemical structures and the chemical structures of the pyridine and azine containing antimitotic compounds are described. The designed principles behind the structural modifications and the achieved effect on the biological activity upon inclusion of these heterocycles are also discussed. Lessons from the achievements and failures have been extracted and future perspectives delineated.

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“…Careful debenzylation of 61 gave labile hemiaminal 62 , which was treated with acetic acid to obtain 4-oxa-2-azapodophyllotoxin 63 (Scheme 7) [22]. Using a similar hypothesis, this group has also synthesized 2,4-diaza-4-deoxypodophyllotoxins 69a–d and 70a–d , where the carbons at the C2 and C4 positions were substituted by nitrogen atoms (Scheme 8) [23, 24]. The objective here was to determine the effect of changes in the whole stereochemical structure on biological properties.…”

Section: Synthesis Of Azapodophyllotoxin Derivativesmentioning

confidence: 99%

“…The N -amino analogues 71 and 72 were also prepared by reacting 69a and 70a , respectively, with O -(2,4-dinitrophenyl)hydroxylamine. Oxidation of 70a was also carried out by reacting it with lead tetraacetate to give the dehydro derivative 73 (Scheme 8) [23, 24]. Later, to evaluate the effect of replacing the methylene group of 1 with nitrogen on biological activity, the same group reported the synthesis of (−)-4-aza-4-deoxypodophyllotoxin ( 74 ) in an optically pure form from natural (−)-podophyllotoxin ( 1 ) through C -ring cleavage followed by a Curtius rearrangement and intramolecular N -alkylation [25].…”

Section: Synthesis Of Azapodophyllotoxin Derivativesmentioning

confidence: 99%

Synthetic and Application Perspectives of Azapodophyllotoxins: Alternative Scaffolds of Podophyllotoxin

Kumar¹,

Kumar²,

Alegrı́a³

et al. 2011

CMC

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Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities.

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Synthesis of 2,4-diaza-4-deoxypodophyllotoxin, a new analogue of podophyllotoxin possessing antitumour activity

Abstract: 2,4-Diaza-4-deox~ypodophyllotoxin 4 and its cis analogue 14 are synthesised stereoselectively from 3,4-methylenedic)xyaniline 5, and show significant activity against vincristine-resistant P-388 leukaemia in vivo.

Cited by 20 publications

References 15 publications

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Synthetic and Application Perspectives of Azapodophyllotoxins: Alternative Scaffolds of Podophyllotoxin

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