Antineoplastic Agents. 291. Isolation and Synthesis of Combretastatins A-4, A-5, and A-6

Pettit, George R.; Singh, Sheo B.; Boyd, Michael R.; Hamel, Ernest; Pettit, Robin K.; Schmidt, Jean M.; Hogan, Fiona

doi:10.1021/jm00010a011

Cited by 396 publications

(308 citation statements)

References 3 publications

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“…Synthesis of the analogous coumarins (Fig. 4) was carried out in the same manner or by treating the bromides 5 and 7, synthesized by phosphorus tribromide bromination of the alcohols, with silver (I) oxide and 7-hydroxy-4-methylcoumarin (3).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Thomson

Naylor

Everett

et al. 2006

Molecular Cancer Therapeutics

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Nitrothienylprop-2-yl ether formation on the 3 ¶-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized following model kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promising new lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl A-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drug release. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the A-carbon. Cellular and supersomal studies showed that this A-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug. [Mol Cancer Ther 2006;5(11):2886 -94]

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Thomson

Naylor

Everett

et al. 2006

Molecular Cancer Therapeutics

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“…The DMU 212 analogues to be used for metabolite identification of 4,4 0 -dihydroxy-3,5-dimethoxystilbene (4,4 0 -di-desmethyl-DMU 212, DMU 295), 4 0 -hydroxy-3,4,5-trimethoxystilbene (4 0 -desmethyl-DMU 212, DMU 281), 4-hydroxy-3,5,4 0 -trimethoxystilbene (4-desmethyl-DMU 212, DMU 291) and 3-hydroxy-4,5,4 0 -trimethoxystilbene (3-desmethyl-DMU 212, DMU 807) (for structures, see Figure 2) were synthesised in a similar fashion using the tert-butylmethylsilylprotected Wittig precursors, and final deprotection with tetrabutylammonium fluoride (Potter et al, 1999). 3 0 -Hydroxy-3,4,5,4 0 -tetramethoxystilbene (3 0 -hydroxy-DMU 212, DMU 214, trans isomer of combretastatin A4) was synthesised according to the method of Pettit et al (1995). The identity of newly synthesised compounds was confirmed by mass spectrometry, nuclear magnetic resonance spectrometry and infrared and ultraviolet spectroscopy.…”

Section: Reagents Animals and Cellsmentioning

confidence: 99%

Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene

et al. 2004

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Resveratrol (trans-3,5,4 0 -trihydroxystilbene) is a naturally occurring polyphenol with cancer chemopreventive properties in preclinical models of carcinogenesis, including those of colorectal cancer. Recently, a variety of analogues of resveratrol have been synthesised and investigated in in vitro assays. One analogue, 3,4,5,4 0 -tetramethoxystilbene (DMU 212), showed preferential growth-inhibitory and proapoptotic properties in transformed cells, when compared with their untransformed counterparts. As part of a chemoprevention drug development programme, the pharmacokinetic properties of DMU 212 were compared with those of resveratrol in the plasma, liver, kidney, lung, heart, brain and small intestinal and colonic mucosa of mice. DMU 212 or resveratrol (240 mg kg À1 ) were administered intragastrically, and drug concentrations were measured by HPLC. Metabolites were characterised by cochromatography with authentic reference compounds and were identified by mass spectrometry. The ratios of area of plasma or tissue concentration vs time curves of resveratrol over DMU 212 (AUC res /AUC DMU212 ) for the plasma, liver, small intestinal and colonic mucosa were 3.5, 5, 0.1 and 0.15, respectively. Thus, resveratrol afforded significantly higher levels than DMU 212 in the plasma and liver, while DMU 212 exhibited superior availability compared to resveratrol in the small intestine and colon. Resveratrol was metabolised to its sulphate or glucuronate conjugates, while DMU 212 underwent metabolic hydroxylation or single and double O-demethylation. DMU 212 and resveratrol inhibited the growth of human-derived colon cancer cells HCA-7 and HT-29 in vitro with IC 50 values of between 6 and 26 mM. In the light of the superior levels achieved in the gastrointestinal tract after the administration of DMU 212, when compared to resveratrol, the results provide a good rationale to evaluate DMU 212 as a colorectal cancer chemopreventive agent.

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“…However, the extent to which this correlation is based on interaction with tubulin remains unclear, as is illustrated by the second section of results obtained with 2-4, 6 and 7 (Table 3b). Matrix COMPARE coefficients (r values) less than 0.6 are of questionable significance, 43,44 and there is considerable variation in the coefficient values across the whole matrix, ranging from notable homology (2 with 3; 3 with 6; 6 with 7) to almost complete disparity with N-acetylcolchinol 4, which in turn shows a modest correlation with 16. Taken together, these results provide a reminder that the relationship between cytotoxicity (or cytostaticity) and the ability to shutdown vasculature remains obscure.…”

Section: 2 In V Itro S C R E E N I N G Ag a In St Nci-60 Cell mentioning

confidence: 99%

Tubulin-binding dibenz[c,e]oxepines: Part 2. Structural variation and biological evaluation as tumour vasculature disrupting agents

Rossington

Hadfield

Shnyder

et al. 2017

Bioorganic & Medicinal Chemistry

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5,7-Dihydro-3,9,10,11-tetramethoxybenz[c,e]oxepin-4-ol 1, prepared from a dibenzyl ether precursor via Pd-catalysed intramolecular direct arylation, possesses broad-spectrum in vitro cytotoxicity towards various tumour cell lines, and induces vascular shutdown, necrosis and growth delay in tumour xenografts in mice at sub-toxic doses. The biological properties of 1 and related compounds can be attributed to their ability to inhibit microtubule assembly at the micromolar level, by binding reversibly to the same site of the tubulin -heterodimer as colchicine 2 and the allocolchinol, N-acetylcolchinol 4.

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Antineoplastic Agents. 291. Isolation and Synthesis of Combretastatins A-4, A-5, and A-6

Cited by 396 publications

References 3 publications

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene

Tubulin-binding dibenz[c,e]oxepines: Part 2. Structural variation and biological evaluation as tumour vasculature disrupting agents

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