I'm an old scientist still working in natural products with two main targets: obesity and metastasis resolution.Any information on these targets are on my interest. Bombardelli
A high-sensitive ELISA method was developed for the detection and semi-quantitative determination... more A high-sensitive ELISA method was developed for the detection and semi-quantitative determination of 10-deacetylbaccatin III and its structurally related compounds in crude extract of Taxus sp. plants and tissue cultures. The antibodies were raised in rabbits using 7- or 10-succinyl-10-deacetylbaccatin III-BSA conjugate as immunogen. The working range of the assay was from 0.003 to 1.000 ng (0.09 to 31.33 nM) of 10-deacetylbaccatin III per assay. The cross-reacting material in crude plant extract was examined by chromatographic (silica gel CC, HPLC) and immunoassay methods. Study on the evaluation of cross-reacting material in crude Taxus plant extracts showed that at least 80% of the immunosignal correspond to 10-deacetylbaccatin III in the extract. The ELISA method was applied to investigate the 10-deacetylbaccatin III equivalent content in crude extracts of 19 plants species including Taxaceae, Taxodiaceae and Pinaceae species. The 10-deacetylbaccatin III-like structure was only detected in Taxus and Torreya sp. The results indicate that this immunoassay is a useful tool for the rapid screening of species, varieties or individual plants out of a wide population. The distribution of 10-deacetylbaccatin III equivalent content in 9-month old Taxus plantlets cultivated in vitro as well as in callus culture was investigated.
Paclitaxel, docetaxel and a series of new analogs synthesized from 14beta-hydroxy-10-deacetylbacc... more Paclitaxel, docetaxel and a series of new analogs synthesized from 14beta-hydroxy-10-deacetylbaccatin III (14-OH-DAB), a natural diterpene closely related to the core synthon of the 2 above prototypes, were tested in vitro for their growth-inhibitory activity on different human cancer cell lines, including some expressing the classic multidrug-resistant (MDR) phenotype (MCF-7 ADRr and CEM VBLr). The 14-OH-DAB derivatives showed enhanced anti-proliferative activity as compared to the parent compounds on the MDR-positive cancer cell lines. Particularly, IDN 5109 showed a 25- to 30-fold higher activity than paclitaxel. The fold change in activity between paclitaxel and analogs (IC50 paclitaxel/IC50 analogs) on the MDR-positive cell lines was calculated and a significant correlation observed. As far as the MDR-negative MDA-MB 231 cells are concerned, docetaxel and IDN 5109 exhibited a more potent activity than paclitaxel. On the basis of the data obtained on cell growth inhibition, we selected the most active compounds to study their effect on the cell cycle. Cell cycle analysis showed that all of the compounds tested were able to induce cell cycle block at G2/M in a concentration-dependent manner. The amount of cell block, measured as a G1/G2 ratio, was correlated significantly (p < 0.001) with apoptosis, as evaluated in the sub-G1 region (% of DNA fragmentation), thereby suggesting that the G2/M-blocked cells underwent apoptosis. To confirm the occurrence of apoptosis in this system, DNA gel agarose electrophoresis was performed and showed the typical ladder pattern.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
2390 Background: The novel thiocolchicine dimer IDN5404 was selected for its activity in human ov... more 2390 Background: The novel thiocolchicine dimer IDN5404 was selected for its activity in human ovarian subline resistant to cisplatin and topotecan, A2780-CIS and A2780-TOP. This effect was related to dual mechanisms of action, i.e., microtubule activity as in Vinca alkaloids and a topoisomerase I inhibitory effect different from camptothecin (Raspaglio, 2004, Biochemical Pharmacology, in press). Herein, we further studied in vitro and in vivo activity of IDN5404 in a nanoparticle albumin-bound state (nab-5404). Methods: IDN5404 was tested for cytotoxic activity using the MCF7-S breast carcinoma and its multidrug resistant variant, MCF7-R (pgp+). Its cytotoxicity was also assessed against the NCI-60 human tumor cell line panel. The nanoparticle albumin bound nab-5404 was administered IV using various schedules, to SCID mice implanted sc with a human A121 ovarian tumor xenograft. Results: Against MCF7 cell lines, the parent compound, colchicine, demonstrated tumor growth inhibition with the IC50 value (50% growth inhibitory concentration) for MCF7-S cells at 3.9 ± 0.2 nM. The resistant variant MCF7-R demonstrated an IC50 of 66 ± 8.6 nM, approximately a 17-fold increase due to drug resistance. IDN-5404, demonstrated increased activity against both cell lines, displaying IC50 values of 1.7 ±0.1 and 40 ± 3.8 nM, respectively. These results were confirmed within the NCI 60 human tumor cell line panel with IDN-5404 having a mean IC50 of 10 fold resistance between the MCF7-S and the MCF7-R cell lines. The COMPARE algorithm identified IDN5404 as a tubulin binder similar to Vinca alkaloids, confirming the previous results. In vivo against the A121 ovarian tumor xenograft, efficacy and toxicity of nab-5404 was dose and schedule dependent. Nanoparticle nab-5404 was well tolerated and capable of inducing complete regressions and cures: at 24 mg/kg administered IV qd x 5, 5 of 5 mice were long-term survivors (LTS) with no evidence of tumor. However, increasing the dosage to 30 mg/kg resulted in 5 of 5 toxic deaths. On a q3d x 4 schedule, 30 mg/kg resulted in 4 of 5 mice LTS and at 50 mg/kg, 5 of 5 toxic deaths. Using a q7d x 3 schedule, 40 mg/kg resulted in 3 of 5 mice LTS and at 50 mg/kg, 4 of 4 LTS were noted. Conclusions: IDN5404, a new thiocolchicine dimer with dual mechanism of action showed activity in pgp-expressing, cisplatin and topotecan resistant cell lines. In vivo, nanoparticle albumin bound nab-5404 was active against A121 ovarian xenograft. Anti-tumor activity of nab-5404 in other xenograft tumors is presently being assessed.
A series of newly developed paclitaxel analogues have been tested for their growth inhibitory act... more A series of newly developed paclitaxel analogues have been tested for their growth inhibitory activity on two human breast cancer cell lines, one of which expresses the MDR (multidrug resistance) phenotype. Paclitaxel (taxol) was used as a reference compound. Three new classes of taxanes were analyzed: the cephalomannine compounds, the pyrazoline derivatives and the seco-derivatives. Our results demonstrated an increased antiproliferative activity of pyrazoline derivatives on drug-resistant cancer cells with respect to paclitaxel. These compounds were able to block MDR-bearing MCF-7 ADRr cells in the G2/M phase of cell cycle and, consequently, induce programmed cell death. In keeping with the antiproliferative effects, cells treated with paclitaxel derivatives showed a more pronounced cell cycle arrest than the parent compound paclitaxel. Also, apoptotic cell death, calculated as a percent of DNA fragmentation, occurred to a greater extent in cells exposed to pyrazoline derivatives. The development of new paclitaxel analogues with greater antitumour activity on MDR-positive cells may be useful in selecting new taxanes effective on resistant tumors.
Objective: Prodigest® is the standardized combination of artichoke and ginger extracts. This comb... more Objective: Prodigest® is the standardized combination of artichoke and ginger extracts. This combination was safe and effective in the treatment of functional dyspepsia. However, further evidence could be useful to shed new lights on the effect of Prodigest® on gastric motility. This pilot randomized study on healthy volunteers investigates the prokinetic activity of Prodigest®. Subjects and methods: This was a randomized, cross-over study in healthy volunteers comparing Prodigest® versus placebo. Eleven healthy volunteers were enrolled. Each participant underwent two evaluations, at a 7-day interval. Ten minutes before the main meal, the baseline area of gastric volume was determined by ultrasonography. The subject was then given one Prodigest® or placebo capsule and, then consumed a standardized meal. One hour after the meal, the gastric volume was measured again. Two weeks after the second evaluation, three subjects repeated the above-mentioned procedures taking two capsules of Prodigest®. Results: The mean gastric area at baseline was 3.2 ± 0.5 cm(2); after the meal, this figure was 8.4 ± 0.7 cm(2) with Prodigest® and 11.0 ± 1.5 cm2 with placebo (p<0.001). The after-meal gastric area was significantly smaller, with a -24% difference, following the combination of extracts, as compared with placebo (p<0.001). The effect of two capsules of Prodigest® seems to be more evident but due to the very small number of the patients sample further clinical data are necessary before confirming the dose-related effects. Conclusions: This pilot study shows that Prodigest®, a standardized extract of ginger and artichoke, significantly promotes gastric emptying in healthy volunteers without being associated with notable adverse effects.
Purpose: The most important variable risk factor for developing glaucoma is intraocular hypertens... more Purpose: The most important variable risk factor for developing glaucoma is intraocular hypertension. Timely lowering of high intraocular pressure (IOP) significantly lowers the likelihood of developing glaucoma. The aim of this study was to evaluate the effects of the food supplement Mirtogenol (Mirtoselect and Pycnogenol on IOP and ocular blood flow in a product evaluation study. Methods: Thirty-eight asymptomatic subjects with intraocular hypertension were either given Mirtogenol (20 subjects) or were not treated (18 subjects). The visual acuity, IOP, and ocular blood flow were measured at two, three, and six months. Results: After two months of supplementation with Mirtogenol, the mean IOP decreased from a baseline of 25.2 mmHg to 22.2 mmHg. After three months of treatment with Mirtogenol, the IOP was significantly lowered compared to that of untreated controls (p<0.05) to 22.0 mmHg. No further improvement was found after six months. Nineteen of the twenty patients taking Mirtogenol had a decreased IOP after three months. Only marginal effects on the IOP were found in the 18 control subjects. No side effects were observed. Ocular blood flow (central retinal, ophthalmic, and posterior ciliary arteries) improved both in the systolic and diastolic components as measured by Color Doppler imaging. After three months of treatment, the improvement of ocular blood flow was significant as compared to both baseline and control group (p<0.05). Conclusions: An improved ocular blood flow may contribute to the prevention of glaucoma. The results of this study indicate that Mirtogenol may represent a safe preventative intervention for lowering the risk for developing symptomatic glaucoma by controlling IOP and improving ocular blood flow.
A HPLC assay was developed to determine IDN 5390, a new paclitaxel analogue, in mouse plasma. The... more A HPLC assay was developed to determine IDN 5390, a new paclitaxel analogue, in mouse plasma. The method involves solid-phase extraction from cyano cartridges (recovery >80%), HPLC separation on Symmetry C(18) (4.6 x 150 mm), on isocratic mobile phase of water-acetonitrile-acetic acid (49:50:1) and detection at 227 nm. Retention times of IDN 5390 and IDN 5517 (internal standard, I.S.) were 9.1 and 10.5 min, respectively. The assay was linear from 0.05 to 5 micro g/ml (r(2)>or=0.995), showed intra- and inter-day precision within 1.0 and 6.2%, and accuracy of 94.7-106.8%. LOQ was 0.050 micro g/ml. Using this method IDN 5390 pharmacokinetics was determined in mice.
Journal of Chromatography B: Biomedical Sciences and Applications, Dec 1, 1999
An HPLC assay was developed to determine the paclitaxel analogue 13-(N-tert.-butoxycarbonyl-β-iso... more An HPLC assay was developed to determine the paclitaxel analogue 13-(N-tert.-butoxycarbonyl-β-isobutylisoserinyl)-14-hydroxybaccatin-1,14-carbonate (IDN5109) and its epimer in mouse plasma. The method involves solid-phase extraction on cyano cartridges (recovery >75%), HPLC separation on symmetry shield column, a mobile phase of NaH2PO4 (10 mM) pH 5.2, acetonitrile (47:53) and detection at 227 nm. Retention times of IDN5109, its epiform and internal standard were 15, 24 and 25.5 min, respectively. The assay was linear from 0.10 to 10 μg/ml (r2=0.999), with a C.V.<5% and accuracy in the range of 95–107%. LOQ was 50 ng/ml for both compounds.Using this method IDN5109 pharmacokinetic was determined in mice.
A conformationally constrained analogue of the paclitaxel side-chain was synthesised in an enanti... more A conformationally constrained analogue of the paclitaxel side-chain was synthesised in an enantioselective way from ethyl 1H-indenc-2-carboxylate. Coupling with 7-triethylsilylbaccatin III and deprotection afforded 2′,2″-methylenepaclitaxel, a novel analogue of the natural product retaining anticancer activity.
... Baccatins via an OxidationReduction Protocol Giovanni Appendino,* Jasmin Jakupovic,b* Giancar... more ... Baccatins via an OxidationReduction Protocol Giovanni Appendino,* Jasmin Jakupovic,b* Giancarlo Cravotto ", Renata Enri6," Marcella Varese" and Ezio Bombardellic a ... For part XX, see:Gabetta, B.; De Bellis, P.; Pace, R.; Appendino, G.; Barboni, L.; Gariboldi, P.; Torregiani, E ...
Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer typ... more Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer types. Paclitaxel blocks cell division by stabilizing microtubules, a mechanism that also underlies its major side effects (neutropenia and neurotoxicity). Paclitaxel can also alter cardiac function, and to elucidate the mechanism of this activity, we tested the mechanical and electrical effects of paclitaxel and a series of analogs (docetaxel, taxol B, taxol C and N-methyltaxol C; 5-20 microM) on two different cardiac preparations, the isolated coronary perfused heart and the papillary muscle of the guinea pig. Paclitaxel and N-methyltaxol C induced conduction arrhythmias and reduced coronary flow and left ventricular systolic pressure in the isolated heart, whereas the other taxol derivatives tested had no significant effect. Moreover, paclitaxel blocked the vasodilator effect of bradykinin in the isolated heart. Paclitaxel and N-methyltaxol C produced a positive inotropic effect in papillary muscle, without alterations in the action potential. In the latter preparation, no significant variations were observed after treatment with the other taxol derivatives. The in vitro cardiodepressant and arrhythmogenic activity of paclitaxel is similar to that reported after its clinical administration and might be due to coronary vasoconstriction. The precise role of microtubules as modulators of intracellular calcium in cardiac and smooth muscle cells is at present unclear, because docetaxel and other taxol analogs, though they exhibited similar activity on tubulin, lacked cardiac effects.
A high-sensitive ELISA method was developed for the detection and semi-quantitative determination... more A high-sensitive ELISA method was developed for the detection and semi-quantitative determination of 10-deacetylbaccatin III and its structurally related compounds in crude extract of Taxus sp. plants and tissue cultures. The antibodies were raised in rabbits using 7- or 10-succinyl-10-deacetylbaccatin III-BSA conjugate as immunogen. The working range of the assay was from 0.003 to 1.000 ng (0.09 to 31.33 nM) of 10-deacetylbaccatin III per assay. The cross-reacting material in crude plant extract was examined by chromatographic (silica gel CC, HPLC) and immunoassay methods. Study on the evaluation of cross-reacting material in crude Taxus plant extracts showed that at least 80% of the immunosignal correspond to 10-deacetylbaccatin III in the extract. The ELISA method was applied to investigate the 10-deacetylbaccatin III equivalent content in crude extracts of 19 plants species including Taxaceae, Taxodiaceae and Pinaceae species. The 10-deacetylbaccatin III-like structure was only detected in Taxus and Torreya sp. The results indicate that this immunoassay is a useful tool for the rapid screening of species, varieties or individual plants out of a wide population. The distribution of 10-deacetylbaccatin III equivalent content in 9-month old Taxus plantlets cultivated in vitro as well as in callus culture was investigated.
Paclitaxel, docetaxel and a series of new analogs synthesized from 14beta-hydroxy-10-deacetylbacc... more Paclitaxel, docetaxel and a series of new analogs synthesized from 14beta-hydroxy-10-deacetylbaccatin III (14-OH-DAB), a natural diterpene closely related to the core synthon of the 2 above prototypes, were tested in vitro for their growth-inhibitory activity on different human cancer cell lines, including some expressing the classic multidrug-resistant (MDR) phenotype (MCF-7 ADRr and CEM VBLr). The 14-OH-DAB derivatives showed enhanced anti-proliferative activity as compared to the parent compounds on the MDR-positive cancer cell lines. Particularly, IDN 5109 showed a 25- to 30-fold higher activity than paclitaxel. The fold change in activity between paclitaxel and analogs (IC50 paclitaxel/IC50 analogs) on the MDR-positive cell lines was calculated and a significant correlation observed. As far as the MDR-negative MDA-MB 231 cells are concerned, docetaxel and IDN 5109 exhibited a more potent activity than paclitaxel. On the basis of the data obtained on cell growth inhibition, we selected the most active compounds to study their effect on the cell cycle. Cell cycle analysis showed that all of the compounds tested were able to induce cell cycle block at G2/M in a concentration-dependent manner. The amount of cell block, measured as a G1/G2 ratio, was correlated significantly (p &amp;amp;lt; 0.001) with apoptosis, as evaluated in the sub-G1 region (% of DNA fragmentation), thereby suggesting that the G2/M-blocked cells underwent apoptosis. To confirm the occurrence of apoptosis in this system, DNA gel agarose electrophoresis was performed and showed the typical ladder pattern.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
2390 Background: The novel thiocolchicine dimer IDN5404 was selected for its activity in human ov... more 2390 Background: The novel thiocolchicine dimer IDN5404 was selected for its activity in human ovarian subline resistant to cisplatin and topotecan, A2780-CIS and A2780-TOP. This effect was related to dual mechanisms of action, i.e., microtubule activity as in Vinca alkaloids and a topoisomerase I inhibitory effect different from camptothecin (Raspaglio, 2004, Biochemical Pharmacology, in press). Herein, we further studied in vitro and in vivo activity of IDN5404 in a nanoparticle albumin-bound state (nab-5404). Methods: IDN5404 was tested for cytotoxic activity using the MCF7-S breast carcinoma and its multidrug resistant variant, MCF7-R (pgp+). Its cytotoxicity was also assessed against the NCI-60 human tumor cell line panel. The nanoparticle albumin bound nab-5404 was administered IV using various schedules, to SCID mice implanted sc with a human A121 ovarian tumor xenograft. Results: Against MCF7 cell lines, the parent compound, colchicine, demonstrated tumor growth inhibition with the IC50 value (50% growth inhibitory concentration) for MCF7-S cells at 3.9 ± 0.2 nM. The resistant variant MCF7-R demonstrated an IC50 of 66 ± 8.6 nM, approximately a 17-fold increase due to drug resistance. IDN-5404, demonstrated increased activity against both cell lines, displaying IC50 values of 1.7 ±0.1 and 40 ± 3.8 nM, respectively. These results were confirmed within the NCI 60 human tumor cell line panel with IDN-5404 having a mean IC50 of 10 fold resistance between the MCF7-S and the MCF7-R cell lines. The COMPARE algorithm identified IDN5404 as a tubulin binder similar to Vinca alkaloids, confirming the previous results. In vivo against the A121 ovarian tumor xenograft, efficacy and toxicity of nab-5404 was dose and schedule dependent. Nanoparticle nab-5404 was well tolerated and capable of inducing complete regressions and cures: at 24 mg/kg administered IV qd x 5, 5 of 5 mice were long-term survivors (LTS) with no evidence of tumor. However, increasing the dosage to 30 mg/kg resulted in 5 of 5 toxic deaths. On a q3d x 4 schedule, 30 mg/kg resulted in 4 of 5 mice LTS and at 50 mg/kg, 5 of 5 toxic deaths. Using a q7d x 3 schedule, 40 mg/kg resulted in 3 of 5 mice LTS and at 50 mg/kg, 4 of 4 LTS were noted. Conclusions: IDN5404, a new thiocolchicine dimer with dual mechanism of action showed activity in pgp-expressing, cisplatin and topotecan resistant cell lines. In vivo, nanoparticle albumin bound nab-5404 was active against A121 ovarian xenograft. Anti-tumor activity of nab-5404 in other xenograft tumors is presently being assessed.
A series of newly developed paclitaxel analogues have been tested for their growth inhibitory act... more A series of newly developed paclitaxel analogues have been tested for their growth inhibitory activity on two human breast cancer cell lines, one of which expresses the MDR (multidrug resistance) phenotype. Paclitaxel (taxol) was used as a reference compound. Three new classes of taxanes were analyzed: the cephalomannine compounds, the pyrazoline derivatives and the seco-derivatives. Our results demonstrated an increased antiproliferative activity of pyrazoline derivatives on drug-resistant cancer cells with respect to paclitaxel. These compounds were able to block MDR-bearing MCF-7 ADRr cells in the G2/M phase of cell cycle and, consequently, induce programmed cell death. In keeping with the antiproliferative effects, cells treated with paclitaxel derivatives showed a more pronounced cell cycle arrest than the parent compound paclitaxel. Also, apoptotic cell death, calculated as a percent of DNA fragmentation, occurred to a greater extent in cells exposed to pyrazoline derivatives. The development of new paclitaxel analogues with greater antitumour activity on MDR-positive cells may be useful in selecting new taxanes effective on resistant tumors.
Objective: Prodigest® is the standardized combination of artichoke and ginger extracts. This comb... more Objective: Prodigest® is the standardized combination of artichoke and ginger extracts. This combination was safe and effective in the treatment of functional dyspepsia. However, further evidence could be useful to shed new lights on the effect of Prodigest® on gastric motility. This pilot randomized study on healthy volunteers investigates the prokinetic activity of Prodigest®. Subjects and methods: This was a randomized, cross-over study in healthy volunteers comparing Prodigest® versus placebo. Eleven healthy volunteers were enrolled. Each participant underwent two evaluations, at a 7-day interval. Ten minutes before the main meal, the baseline area of gastric volume was determined by ultrasonography. The subject was then given one Prodigest® or placebo capsule and, then consumed a standardized meal. One hour after the meal, the gastric volume was measured again. Two weeks after the second evaluation, three subjects repeated the above-mentioned procedures taking two capsules of Prodigest®. Results: The mean gastric area at baseline was 3.2 ± 0.5 cm(2); after the meal, this figure was 8.4 ± 0.7 cm(2) with Prodigest® and 11.0 ± 1.5 cm2 with placebo (p<0.001). The after-meal gastric area was significantly smaller, with a -24% difference, following the combination of extracts, as compared with placebo (p<0.001). The effect of two capsules of Prodigest® seems to be more evident but due to the very small number of the patients sample further clinical data are necessary before confirming the dose-related effects. Conclusions: This pilot study shows that Prodigest®, a standardized extract of ginger and artichoke, significantly promotes gastric emptying in healthy volunteers without being associated with notable adverse effects.
Purpose: The most important variable risk factor for developing glaucoma is intraocular hypertens... more Purpose: The most important variable risk factor for developing glaucoma is intraocular hypertension. Timely lowering of high intraocular pressure (IOP) significantly lowers the likelihood of developing glaucoma. The aim of this study was to evaluate the effects of the food supplement Mirtogenol (Mirtoselect and Pycnogenol on IOP and ocular blood flow in a product evaluation study. Methods: Thirty-eight asymptomatic subjects with intraocular hypertension were either given Mirtogenol (20 subjects) or were not treated (18 subjects). The visual acuity, IOP, and ocular blood flow were measured at two, three, and six months. Results: After two months of supplementation with Mirtogenol, the mean IOP decreased from a baseline of 25.2 mmHg to 22.2 mmHg. After three months of treatment with Mirtogenol, the IOP was significantly lowered compared to that of untreated controls (p<0.05) to 22.0 mmHg. No further improvement was found after six months. Nineteen of the twenty patients taking Mirtogenol had a decreased IOP after three months. Only marginal effects on the IOP were found in the 18 control subjects. No side effects were observed. Ocular blood flow (central retinal, ophthalmic, and posterior ciliary arteries) improved both in the systolic and diastolic components as measured by Color Doppler imaging. After three months of treatment, the improvement of ocular blood flow was significant as compared to both baseline and control group (p<0.05). Conclusions: An improved ocular blood flow may contribute to the prevention of glaucoma. The results of this study indicate that Mirtogenol may represent a safe preventative intervention for lowering the risk for developing symptomatic glaucoma by controlling IOP and improving ocular blood flow.
A HPLC assay was developed to determine IDN 5390, a new paclitaxel analogue, in mouse plasma. The... more A HPLC assay was developed to determine IDN 5390, a new paclitaxel analogue, in mouse plasma. The method involves solid-phase extraction from cyano cartridges (recovery >80%), HPLC separation on Symmetry C(18) (4.6 x 150 mm), on isocratic mobile phase of water-acetonitrile-acetic acid (49:50:1) and detection at 227 nm. Retention times of IDN 5390 and IDN 5517 (internal standard, I.S.) were 9.1 and 10.5 min, respectively. The assay was linear from 0.05 to 5 micro g/ml (r(2)>or=0.995), showed intra- and inter-day precision within 1.0 and 6.2%, and accuracy of 94.7-106.8%. LOQ was 0.050 micro g/ml. Using this method IDN 5390 pharmacokinetics was determined in mice.
Journal of Chromatography B: Biomedical Sciences and Applications, Dec 1, 1999
An HPLC assay was developed to determine the paclitaxel analogue 13-(N-tert.-butoxycarbonyl-β-iso... more An HPLC assay was developed to determine the paclitaxel analogue 13-(N-tert.-butoxycarbonyl-β-isobutylisoserinyl)-14-hydroxybaccatin-1,14-carbonate (IDN5109) and its epimer in mouse plasma. The method involves solid-phase extraction on cyano cartridges (recovery >75%), HPLC separation on symmetry shield column, a mobile phase of NaH2PO4 (10 mM) pH 5.2, acetonitrile (47:53) and detection at 227 nm. Retention times of IDN5109, its epiform and internal standard were 15, 24 and 25.5 min, respectively. The assay was linear from 0.10 to 10 μg/ml (r2=0.999), with a C.V.<5% and accuracy in the range of 95–107%. LOQ was 50 ng/ml for both compounds.Using this method IDN5109 pharmacokinetic was determined in mice.
A conformationally constrained analogue of the paclitaxel side-chain was synthesised in an enanti... more A conformationally constrained analogue of the paclitaxel side-chain was synthesised in an enantioselective way from ethyl 1H-indenc-2-carboxylate. Coupling with 7-triethylsilylbaccatin III and deprotection afforded 2′,2″-methylenepaclitaxel, a novel analogue of the natural product retaining anticancer activity.
... Baccatins via an OxidationReduction Protocol Giovanni Appendino,* Jasmin Jakupovic,b* Giancar... more ... Baccatins via an OxidationReduction Protocol Giovanni Appendino,* Jasmin Jakupovic,b* Giancarlo Cravotto ", Renata Enri6," Marcella Varese" and Ezio Bombardellic a ... For part XX, see:Gabetta, B.; De Bellis, P.; Pace, R.; Appendino, G.; Barboni, L.; Gariboldi, P.; Torregiani, E ...
Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer typ... more Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer types. Paclitaxel blocks cell division by stabilizing microtubules, a mechanism that also underlies its major side effects (neutropenia and neurotoxicity). Paclitaxel can also alter cardiac function, and to elucidate the mechanism of this activity, we tested the mechanical and electrical effects of paclitaxel and a series of analogs (docetaxel, taxol B, taxol C and N-methyltaxol C; 5-20 microM) on two different cardiac preparations, the isolated coronary perfused heart and the papillary muscle of the guinea pig. Paclitaxel and N-methyltaxol C induced conduction arrhythmias and reduced coronary flow and left ventricular systolic pressure in the isolated heart, whereas the other taxol derivatives tested had no significant effect. Moreover, paclitaxel blocked the vasodilator effect of bradykinin in the isolated heart. Paclitaxel and N-methyltaxol C produced a positive inotropic effect in papillary muscle, without alterations in the action potential. In the latter preparation, no significant variations were observed after treatment with the other taxol derivatives. The in vitro cardiodepressant and arrhythmogenic activity of paclitaxel is similar to that reported after its clinical administration and might be due to coronary vasoconstriction. The precise role of microtubules as modulators of intracellular calcium in cardiac and smooth muscle cells is at present unclear, because docetaxel and other taxol analogs, though they exhibited similar activity on tubulin, lacked cardiac effects.
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