Synthesis of water-soluble prodrugs of the cytotoxic agent Combretastatin A4

Bedford, Simon B; Quarterman, Charmaine P.; Rathbone, Daniel L.; Slack, Joan; Griffin, Roger J.; Stevens, Malcolm F. G.

doi:10.1016/0960-894x(95)00580-m

Cited by 33 publications

(24 citation statements)

References 5 publications

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“…The methoxy group in the B ring of 3-aminobenzophenones should be present at the C-4 position (30) for maximal cytotoxicity, shifting it to C-5 (29) resulted in 5-10 fold decrease in activity. The size of the alkoxy substitution at C-4 was also important, though the ethoxy substituted compound 31 retained the cytotoxicity, any further increase in bulk (32,33) resulted in substantial loss of activity. Examination of the SAR in aminobenzophenone analogues revealed that introduction of an amino group in the B ring plays an integral role for maximal cytotoxicity though its position appears to be more flexible as compared to methoxy group, either at the C-2 or C-3 position [73].…”

Section: (A) Carbonyl Bridgehead Analoguesmentioning

confidence: 97%

“…The sparing water solubility of CA-4 and its alkali metal salts, resulted in poor bioavailability and unsatisfactory drug formulations. Prodrug approaches were adopted by various research groups to overcome this problem [21,[33][34][35]. CA4P, the disodium phosphate prodrug developed by Pettit et al, with excellent water solubility, good stability and cell growth inhibitory activity comparable to CA-4 was selected for the drug formulation studies and subsequently for the phase I/II clinical trials.…”

Section: Combretastatinsmentioning

confidence: 99%

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Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

Hsieh

Liou²,

Mahindroo

2005

CPD

149

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The design of novel anticancer agents based on the combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz, is of considerable contemporary interest. Combretastatin A-4, the most active compound in the group, due to its unique dual features of antitubulin and antivascular properties, has drawn significant attention of medicinal chemists for the design of analogues as novel antitumor agents. To date, 252 references have been published since 1982 and 187 references have been published since 1998 related to combretastatins research. The 102 references related to chemistry efforts can be classified into three different categories including one-atom, two-atom, and three-atom bridgeheads as linker between two aryl rings of combretastatins. This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.

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Section: (A) Carbonyl Bridgehead Analoguesmentioning

confidence: 97%

Section: Combretastatinsmentioning

confidence: 99%

Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

Hsieh

Liou²,

Mahindroo

2005

CPD

149

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“…6 Seven-day-old mice (P7) and nursing dams were placed in an airtight chamber and exposed to 75% O 2 (Ϯ2%, flow rate 1 L/min) for 5 days, when mice were removed from the chamber and returned to ambient conditions. After 24 hours, daily treatment with 0.78, 1.56, 3.125, 6.25, or 12.0 mg/kg CA-4P (intraperitoneally, total injection volume of 20 l, synthesized as previously described [15][16][17] ) was commenced. At P17, mice were killed and eyes were enucleated, fixed in neutral-buffered formalin for 24 hours and processed for paraffin sectioning.…”

Section: Drug Treatment Of Mice With Proliferative Retinopathymentioning

confidence: 99%

Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4

Griggs

Skepper

Smith

et al. 2002

The American Journal of Pathology

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Retinal neovascularization occurs in a variety of diseases including diabetic retinopathy, the most common cause of blindness in the developed world. There is accordingly considerable incentive to develop drugs that target the aberrant angiogenesis associated with these conditions. Previous studies have shown that a number of anti-angiogenic agents can inhibit retinal neovascularization in a well-characterized murine model of ischemia-induced proliferative retinopathy. Combretastatin-A4 (CA-4) is an anti-vascular tubulin-binding agent currently undergoing clinical evaluation for the treatment of solid tumors. We have recently shown that CA-4 is not tumor-specific but elicits anti-vascular effects in nonneoplastic angiogenic vessels. In this study we have examined the capacity of CA-4 to inhibit retinal neovascularization in vivo. CA-4 caused a dose-dependent inhibition of neovascularization with no apparent side effects. The absence of vascular abnormalities or remnants of disrupted neovessels in retinas of CA-4-treated mice suggests an anti-angiogenic mechanism in this model, in contrast to the anti-vascular effects observed against established tumor vessels. Importantly, histological and immunohistochemical analyses indicated that CA-4 permitted the development of normal retinal vasculature while inhibiting aberrant neovascularization. These data are consistent with CA-4 eliciting tissue-dependent anti-angiogenic effects and suggest that CA-4 has potential in the treatment of nonneoplastic diseases with an angiogenic component.

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“…Both isomers of di-sodium phosphate CA-4 pro-drug were synthesized as previously described (Pettit et al, 1995Bedford et al, 1996;Orsini et al, 1997;, dissolved in saline and filter sterilized. Goitrogen-treated and non-goitrogentreated groups of mice were given either cis-CA-4 phosphate, trans-CA-4 phosphate or no further treatment.…”

Section: Combretastatin Synthesis and Administrationmentioning

confidence: 99%

Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue

et al. 2001

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Summary Combretastatin-A4 phosphate (cis-CA-4) is a tubulin-binding agent currently undergoing clinical trials as an anti-tumour drug. We have investigated whether CA-4 functions as a tumour-specific anti-vascular agent using the hyperplastic thyroid as a novel in vivo model of neovascularization. CA-4 elicited pathological changes in normal tissue, manifested as the induction of multiple, discrete intravascular thrombi. These vascular-damaging effects indicate that CA-4P does not function as a tumour-specific agent but targets neovasculature irrespective of the primary angiogenic stimulus.

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Synthesis of water-soluble prodrugs of the cytotoxic agent Combretastatin A4

Cited by 33 publications

References 5 publications

Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4

Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue

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