Patent Grant
8354547
The present invention relates to novel 4β-amino podophyllotoxin congeners as antitumour antibiotics. More particularly, the present invention relates to novel β-amino podophyllotoxin congeners of general formula A
The present invention also relates to a process for the preparation of 40-amino podophyllotoxin congeners.
Etoposide and teniposide are semi-synthetic podophyllotoxin derivatives that are in clinical usage as an anticancer drugs
The main object of the invention is to provide the novel 4β-amino podophyllotoxin congeners as useful antitumour antibiotics.
Another object of the present invention is to provide a process for the synthesis of these new 4β-amino derivatives of podophyllotoxin as useful anticancer or antitumour agents.
Another object of the present invention is to provide new and stereoselective compounds based on the podophyllotoxin and 4′-O-demethylepipodophyllotoxin in good yields.
Accordingly the present provides novel 4β-amino podophyllotoxin congeners of general formula A as antitumour antibiotics.
In an embodiment of the present invention the novel 4β-amino podophyllotoxin congeners formula A is represented by the following compounds of formula 3a-f and 4a-f
In yet another embodiment the novel 413-amino podophyllotoxin congeners is represented by the following compounds:
The present invention further provides a process for the preparation of 4(3-amino podophyllotoxin congeners of general formula A as antitumour antibiotics
and the said process comprising the steps of:
In still another embodiment the novel 4β-amino podophyllotoxin congeners obtained are useful as antitumour antibiotics.
The process for the synthesis of new podophyllotoxin analogues as anticancer agents produces the novel and stereo-selective derivatives of the podophyllotoxin in good yields, where in the key step for the synthesis of these analogues is by direct nucleophilic substitution of C-4β-iodo intermediates. The 4β-iodopodophyllotoxin, which has been reacted with substituted or unsubstituted polyarylamines in a stereo-selective manner to afford the 4β-polyarylamino derivatives of podophyllotoxin.
These 4-iodopodophyllotoxin intermediates have been prepared by the iodination of the related podophyllotoxin compounds as described in the literature (Kamal, A.; Kumar, B. A.; Arifuddin, M. Tetrahedron Lett. 2003, 44, 8457.).
In an embodiment of the present invention, the naturally occurring podophyllotoxin lignan was isolated from Podophyllunt peltatum linnaeus.
In another embodiment of the present invention the synthesis of 4β-intermediates have been carried out from iodination of podophyllotoxin.
In yet another embodiment of the present invention 1-2 eq. of different unsubstituted and substituted Polyarylamine compounds have been used.
In still another embodiment of the present invention a variety of solvents were used for the nucleophilic substitution step, such as dichloromethane, chloroform and tetrahydrofuran.
In still another embodiment of the present invention bases like K2CO3, Et3N were used.
In still another embodiment of the present invention the purification of these analogues was done by column chromatography employing ethylacetate/hexane as eluent.
Thus the present invention provides new class of podophyllotoxin analogues, which were synthesized in a stereoselective manner.
A program was initiated in the laboratory for the design and synthesis of new 4β-aryl amino substituted podophyllotoxin congeners with enhanced antitumour activity and/or activity against etoposide resistant tumor cell lines. In these efforts new 4β-polyarylamino derivatives of podophyllotoxin have been synthesized and evaluated for their cytotoxicity and anticancer potency compared to adiramycin. The synthesis of these compounds has been carried out as described in the Scheme 1 using podophyllotoxin obtained from the resin.
Some of the compounds of the present invention are given below:
To a solution of podophyllotoxin (414 mg, 1 mmol) in dry acetonitrile (10 mL), sodium iodide (298 mg, 2 mmol) was added and stirred for 5 min to this stirred suspension BF3.Et2 (0.13 mL, 2 mmol) was added dropwise with at 0° C. and the stirring was continued for another 0.5 h at room temperature. This solution was then evaporated in vacuo and used for the next reaction without further purification. To the crude product, anhydrous barium carbonate (395 mg, 2 mmol) and 1-anthraceneamine (231 mg, 1.2 mmol) in 10 mL of dry THF under nitrogen was added and stirred for 8 h at room temperature. The reaction mixture was filtered, diluted with ethyl acetate and washed with water, 10% aqueous sodium thiosulphate solution, dried and purified via column chromatography using ethyl acetate/hexane mixture as eluent to get pure product in 90% yield.
m.p: 195-200° C. [α]25D: −39.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.1 (m, 1H), 3.3 (dd, 1H, J=13.6, 4.53 Hz), 3.78 (s, 6H), 3.8 (s, 3H), 3.97 (t, 1H, J=9.06 Hz), 4.43 (t, 1H, J=8 Hz), 4.67 (d, 2H, J=4.53 Hz), 4.95 (br, 1H), 5.97 (d, 2H, J=3.02 Hz), 6.33 (s, 2H), 6.43 (d, 1H, J=7.55 Hz), 6.6 (s, 1H), 6.8 (s, 1H), 7.28 (m, 1H), 7.43 (m, 3H), 7.94 (m, 2H), 8.24 (s, 1H), 8.35 (s, 1H).
13C NMR (CDCl3): δ 38.78, 42.33, 43.75, 52.54, 56.41, 60.71, 69.0, 101.53, 108.75, 109.3, 110, 118.43, 118.81, 122.97, 125.44, 125.56, 125.85, 126.93, 127.80, 128.24, 130.68, 131.09, 131.82, 132.28, 132.54, 135.22, 142.43, 147.79, 148.40, 152.73, 174.64.
IR (KBr) cm−1: 3409, 2903, 2834, 1774, 1586, 1503, 1481.
MS (FAB): 589 [M+].
To a solution of podophyllotoxin (10) (414 mg, 1 mmol) in dry CH2Cl2 (10 mL), sodium iodide (298 mg, 2 mmol) was added and stirred for 5 min to this stirred suspension BF3.OEt2 (0.13 mL, 2 mmol) was added dropwise with at 0° C. and the stirring was continued for another 5 h at room temperature. Nitrogen was bubbled through the solution to drive of the excess hydrogen iodide. This solution was then evaporated in vacuo and used for the next reaction without further purification. To the above crude product, anhydrous barium carbonate (395 mg, 2 mmol) and 1-anthraceneamine (231 mg, 1.2 mmol) in 10 mL of dry THF under nitrogen was added and stirred for 8 h at room temperature. The reaction mixture was filtered, diluted with ethyl acetate and washed with water, 10% aqueous sodium thiosulphate solution, dried and purified via column chromatography using ethyl acetate/hexane mixture as eluent to get pure product in 65% yield.
m.p: 180-182° C. [α]25D: −59.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.11 (m, 1H), 3.39 (dd, 1H, J=13.6, 4.53 Hz), 3.83 (s, 6H), 3.97 (t, 1H, J=9.1 Hz), 4.46 (t, 1H, J=8.31 Hz), 4.73 (m, 2H), 5.45 (br, 1H), 5.98 (d, 2H, J=1.51 Hz), 6.4 (s, 2H), 6.47 (d, 1H, J=7.55 Hz), 6.63 (s, 1H), 6.82 (s, 1H), 7.35 (m, 1H), 7.48°(m, 3H), 7.97 (m, 2H), 8.24 (s, 1H), 8.35 (s, 1H).
IR (KBr) cm−1: 3416, 2924, 2852, 1773, 1576, 1481. MS (FAB): 575 [M+].
This compound was prepared according to the method described for 3a employing 1-fluorenylamine (220 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 75% yield.
m.p: 209-212° C.; [α]25D: −129.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.07 (m, 1H), 3.2 (dd, J=13.6, 4.53 Hz), 3.77 (s, 6H), 3.82 (s, 3H), 3.84 (s, 2H), 3.92 (br, 1H), 4.07 (t, 1H, J=9.06 Hz), 4.44 (t, 1H, J=8.31 Hz), 4.63 (d, 1H, J=4.53 Hz), 4.76 (m, 1H), 5.98 (d, 2H, J=3.02 Hz), 6.34 (s, 2H), 6.55 (s, 1H), 6.58 (dd, 1H, J=8.31, 2.27 Hz), 6.75 (m, 1H), 6.81 (s, 1H), 7.1-7.7 (m, 5H).
R (KBr) cm−1: 3364, 2906, 2834, 1774, 1615, 1585, 1503, 1457.
MS (FAB): 577 [M+].
This compound was prepared, according to the method described for 4a employing 1-fluorenylamine (220 mg, 12 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 63% yield.
m.p: 250-252° C. [α]25D: −105.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.0-33 (m, 2H), 3.74 (s, 6H), 3.79 (s, 2H), 3.88 (m, 1H), 4.34 (t, 1H, J=7.81 Hz), 4.52 (d, 1H, J=5.21 Hz), 4.86 (m, 1H), 5.96 (s, 2H), 6.28 (s, 2H), 6.5 (s, 1H), 6.67 (m, 1H), 6.81 (s, 1H), 6.86 (m, 1H), 7.06-7.58 (m, 5H).
IR (KBr) cm−1: 3349, 2925, 2854, 1758, 1610, 1515, 1458.
MS (FAB): 563 [M+].
This compound was prepared according to the method described for 3a employing 1-pyrenylamine (265 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 67% yield.
m.p: 190-193° C.; [α]25D: −122.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.19 (m, 1H); 3.34 (dd, 1H, J=14.16, 5.39 Hz), 3.82 (s, 6H), 3.84 (s, 3H), 4.02 (t, 1H, J=10.11 Hz), 4.5 (t, 1H, J=8.09 Hz), 4.7 (d, 1H, J=4.72 Hz), 4.86 (m, 1H), 5.11 (m, 1H), 6.01 (s, 2H), 6.37 (s, 2H), 6.62 (s, 1H), 6.83 (s, 1H), 7.1-8.1 (m, 9H).
IR (KBr) cm−1: 3394, 2924, 1770, 1615, 1505, 1483.
MS (FAB): 617 [M+].
This compound was prepared according to the method described for 4a employing 1-pyrenylamine (265 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 55% yield.
m.p: 148-153° C. [α]25D: −76.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.13 (m, 1H), 3.29 (dd, 1H, J=13.6, 4.53 Hz), 3.83 (s, 6H), 3.98 (t, 1H, J=10.57 Hz), 4.44 (t, 1H, J=8.31 Hz), 4.55 (m, 1H), 4.66 (d, 1H, J=5.29 Hz), 5.07 (m, 1H), 5.34 (br, 1H), 5.97 (s, 2H), 6.35 (s, 2H), 6.59 (s, 1H), 6.8 (s, 1H), 7.18 (m, 1H), 7.9 (m, 8 Hz).
IR (KBr) cm−1: 3381, 2920, 1775, 1603, 1510, 1483.
MS (FAB): 603 [M+].
This compound was prepared according to the method described for 3a employing 6-chrycenylamine (296 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 71% yield.
m.p: 157-160° C. [α]25D: −48.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.3 (m, 2H), 3.82 (s, 6H), 3.83 (s, 3H), 4.07 (t, 1H.; J=9.51 Hz), 4.61 (t, 2H, J=7.13 Hz), 4.72 (m, 2H), 5.21 (m, 1H), 6.0 (d, 2H, J=2.38 Hz), 6.38 (s, 2H), 6.57 (s, 1H), 6.86 (s, 1H), 7.4-9.0 (m, 11H).
IR (KBr) cm−1: 3409, 2906, 1774, 1598, 1503, 1483.
MS (FAB): 643 [M+].
This compound was prepared according to the method described for 4a employing 6-chrycenylamine (296 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 52% yield.
m.p: 158-160° C. [α]25D: −39.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.34 (m, 2H), 3.84 (s, 6H), 4.08 (t, 1H, J=102 Hz), 4.59 (m, 1H), 4.74 (m, 2H), 5.21 (m, 1H), 5.98 (s, 2H,), 6.34 (s, 2H), 6.51 (s, 1H), 6.83 (s, 1H), 7.4-9.0 (m, 11H).
IR (KBr) cm−1: 3394, 2923, 1768, 1615, 1503, 1482.
MS (FAB): 629 [M+].
This compound was prepared according to the method described for 3a employing 4-amino-4′-fluorobenzophenone (258 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 75% yield.
m.p: 106-110° C. [α]25D: −106.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.02 (m, 2H), 3.75 (s, 6H), 3.78 (s, 3H), 4.4 (m, 2H), 4.58 (m, 1H), 4.8 (m, 1H), 5.95 and 5.98 (ABq, 2H, J=1.51 Hz), 6.25 (s, 2H), 6.55 (m, 3H), 6.78 (s, 1H), 7.12 (m, 2H), 7.72 (m, 4H).
IR (KBr) cm−1: 3348, 2923, 1772, 1641, 1596, 1504, 1481.
MS (FAB): 611 [M+].
This compound was prepared according to the method described for 4a employing 4-amino-4′-fluorobenzophenone (258 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 65% yield.
m.p: 162-165° C. [α]25D: −129.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.02 (m, 2H), 3.79 (s, 6H), 4.36 (m, 1H), 4.52 (m, 2H), 4.79 (m, 1H), 5.35 (br, 1H), 5.95 and 5.98 (ABq, 2H, J=1.51 Hz), 6.28 (s, 2H), 6.51 (s, 1H), 6.57 (d, 2H, J=8.69 Hz), 6.76 (s, 1H), 7.13 (m, 2H), 7.68-7.79 (m, 4H).
IR (KBr) cm−1: 3402, 2924, 1775, 1610, 1503, 1481.
MS (FAB): 597 [M+].
This compound was prepared according to the method described for 3a employing 4-amino-4′-[di(2-chloroethyl)amino]benzophenone (404 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 65% yield.
m.p: 186-190° C. [α]25D: −110.0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.13 (m, 2H), 3.64-3.91 (m, 17H), 3.99 (m, 1H), 4.26-4.48 (m, 2H), 4.63 (m, 1H), 4.81 (m, 1H), 5.99 (d, 2H, J=6.8 Hz), 6.33 (s, 2H), 6.55 (s, 1H), 6.57-6.74 (m, 4H), 6.8 (s, 1H), 7.66-7.8 (m, 4H).
IR (KBr) cm−1: 3380, 2924, 2854, 1773, 1727, 1596, 1507, 1480.
MS (FAB): 733 [M+].
This compound was prepared according to the method described for 4a employing 4-amino-4′-[di(2-chloroethyl)amino]benzophenone (404 mg, 1.2 mmol) and podophyllotoxin (414 mg, 1 mmol) to get pure product in 51% yield.
m.p: 173-175° C. [α]25D: −124:0 (c=1.0, CHCl3)
1H NMR (CDCl3): δ 3.12 (m, 2H), 3.65-3.88 (m, 14H), 3.99 (t, 1H, J=10.57 Hz), 4.48 (m, 2H), 4.62 (d, 1H, J=4.53 Hz), 4.82 (m, 1H), 5.34 (br, 1H), 5.98 (d, 2H, J=6.8 Hz), 6.33 (s, 2H), 6.55 (s, 1H), 6.57-6.74 (m, 4H), 6.8 (s, 1H), 7.66-7.8 (m, 4H).
IR (KBr) cm−1: 3395, 2920, 1772, 1598, 1507, 1481.
MS (FAB): 719 [M+].
Biological Activity:
In Vitro Evaluation of Cytotoxic Activity
Compounds 3a-f and 4a-f have been evaluated for their in vitro cytotoxicity in selected human cancer cell lines i.e., Liver (HEP-2), Neuroblastoma (IMR-32), Breast (MCF-7), CNS (SK-N-SH) and Colon (Colo-205, SW-620) origin by employing the sulforhodamine B (SRB) assay method (Skehn, P.; Storeng, R.; Scudiero, A.; Monks, J.; McMohan, D.; Vistica, D.; Jonathan, T. W.; Bokesch, H.; Kenney, S.; Boyd M. R. J. Natl. Cancer Inst. 1990, 82, 1107). The results (μM/ml) are summarized with standard drug Adriamycin in Table-1. All the new compounds were significantly cytotoxic towards the liver, CNS and colan cancer cell lines compared, to the standard drug tested, with the fixed concentration of the drug (10 μM).
Apart from this, some of these analogues were evaluated for Topoisomerase-I relaxation, Topoisomerase-II inhibition, DNA laddering assay and DNA cell cycle analysis. Compounds 3c, 4c, 3d and 4d were analyzed for topoisomerase-I assay at 100 μM (
Compound 3d evaluated for DNA laddering assay. This compound at 0.5, 1, 5, and 10 μM concentration induced DNA fragmentation in leukemia (MOLT-4) cells after 24 hr incubation (
Procedure of the SRB-Assay
Single cell suspension of the tumor cells grown in tissue culture were made, cells counted and cell count adjusted to 1×105 to 5×105 Ninetysix (96) well plates were seeded with this cell suspension, each well receiving 100 μl of it. The plate was then be incubated at 37° C. temperature in CO2 incubator for 24 hours. Drugs were added at appropriate concentrations after 24-hour, incubation followed by further incubation for 48 hours. Experiment was terminated by gently layering the cells in the wells with 30% TCA and plates were kept in refrigerator for 1 hour following which they were washed thoroughly with tap water, dried attained with 0.4% SRB in 1% acetic aid and finally, the bound SRB eluted with 10 mM tris. Absorbance was read at 540 nm, in the microtitre-plate reader. Optical density of drug-treated cells was compared with that of control cells and cell inhibition was calculated as percent values. Each compound was tested at 10, 20, 40 and 80 μg/ml in triplicate on human malignant cell lines.
Topoisomerase-I Relaxation Assay
Reaction was assembled in micro centrifuge tube that contains super coiled DNA 250 ng/μl & Topoisomerase-I (4 units) in assay buffer (10 mM Tris-HCl, pH 7.9, 0.15 M NaCl, 0.1% BSA, and 5.0 mM (beta)-mercaptoethanol). In each reaction 2 μl sample was added then volume was made up to 20 μl with water and then incubated at 37° C. Reaction was terminated by addition of 2 μl of 10% SDS. Each sample tube was treated with proteinase K and extracted once with chloroform: isoamyl alcohol. Products were resolved by 0.8% agarose gel electrophoresis in TAE buffer (40 mM tris-acetate, pH 8.0, and 1 mM EDTA) and stained with 0.5 μg/ml ethedium bromide (EtBr). Results are shown in
DNA Topoisomerase-II Inhibition Assay
Reaction was assembled in micro centrifuge tube that contains super coiled DNA 250 ng/μl & Topoisomerase-I (4 units) in assay buffer (A 0.1 volume and B 1 volume)). In each reaction 2 μl sample was added then volume was made up to 20 μl with water and then incubated at 37° C. Reaction was terminated by addition of 2 μl of 10% SDS. Each sample tube was treated with proteinase K and extracted once with chloroform: isoamyl alcohol. Products were resolved by 0.8% agarose gel electrophoresis in TAE buffer (40 mM tris-acetate, pH 8.0, and 1 mM. EDTA) and stained with 0.5 μg/ml, ethedium bromide (EtBr). Results are shown in
DNA Gel Electophoresis
DNA fragmentation was determined by electrophoresis of extracted genomic DNA form leukemia cell (MOLT4). Briefly, exponentially growing cells (2×106 cells/mL) in 6 well plate were treated with compound 3d in 0.5, 1, 5 and 10 μM concentrations for 24 hrs. Cells were harvested, washed with PBS, pellets were dissolved in lyris buffer (10 mM EDTA, 50 mM Tris pH 8.0, 0.5% w/v SDS and proteinase K (0.5 mg/mL) and incubated at 50° C. for 1 hr. Finally the DNA obtained was heated rapidly to 70° C., supplemented with loading dye and immediately resolved on to 1.5% agarose gel at 50 V for 2-3 hrs (
Flow-Cytometric Analysis of Phase Distribution of Nuclear DNA
Effect of compound 3d on DNA content by cell cycle phase distribution was assessed using HL-60 cells by incubating the HL-60 cells (1×106) 1 ml phosphate buffer saline were treated with 3d (0.5, 1, 5, 10 μM) for 24 hr. The cells were then washed twice with ice-cold PBS, harvested, fixed with ice cold PBS in 70% ethanol, and stored at −20° C. for 30 minutes. After Fixation, these cells were incubated with RNase A (0.1 mg/ml) at 37° C. for 30 min, stained with propidium iodide (50 μg/ml) for 30 min on ice in dark, and then measured for DNA content using BD-LSR flow cytometer (Becton Dickinson, USA) equipped with electronic doublet discrimination capability using blue (488 nm) excitation from orgon laser. Data were collected in list mode on 10,000 events for FL2-A vs. FL2-W (
In conclusion, the main advantages of the present inventions are that these new 4β-polyarylamine analogues of podophyllotoxin have exhibited promising in vitro cytotoxic activity. Further, these compounds have been prepared from podophyllotoxin upon reaction with BF3.OEt2/NaI followed by the addition of corresponding polyaryl amines in the presence of BaCO3 at room temperature to provide the 4β-polyarylamino podophyllotoxin analogues in very good yields and in almost stereoselective manner.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2535/DEL/2008 | Nov 2008 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN2009/000194 | 3/24/2009 | WO | 00 | 5/4/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/052733 | 5/14/2010 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 5132322 | Lee et al. | Jul 1992 | A |
| 7087641 | Kamal et al. | Aug 2006 | B2 |
| Number | Date | Country |
|---|---|---|
| 03082876 | Oct 2003 | WO |
| 2004033423 | Apr 2004 | WO |
| Entry |
|---|
| Kamal et al. Tetrahedron Letters, 2003, 44, 8457-8459. |
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| Saito, H. et al., “Studies on Lignan Lactone Antitumor Agents. I. Synthesis of Aminoglycosidic Lignan Variants Related to Podophyllotoxin,” Chem. Pharm. Bull., vol. 34, No. 9, pp. 3733-3740 (1986). |
| Chen, Y. Z. et al., “Anticancer Drugs II. Synthesis and Biological Evaluation of Spin Labeled Derivatives of Podophyllotoxin,” Life Sciences, vol. 45, pp. 2569-2575 (1989). |
| Lee, K. H. et al., “Antitumor Agents, 107. New Cytotoxic 4-Alkylamino Analogues of 4′-Demethyl-Epipodophyllotoxin As Inhibitors of Human DNA Topoisomerase II,” Journal Nat. Prod., vol. 52, No. 3, pp. 606-613 (1989). |
| Lee, K. H. et al., “Antitumor Agents. III. New 4-Hydroxylated and 4-Halogenated Anilino Derivatives of 4′Demethylepipodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II,” J. Med. Chem., vol. 33, pp. 1364-1368 (1990). |
| Kamal, A., et al., “Synthesis and biological evaluation of new 4β-anilino- and 4β-imido-substituted podophyllotoxin congeners,” Bioorg. & Med. Chem., vol. 13, pp. 6218-6225 (2005). |
| Kamal, A. et al., “Synthesis of 4β-amido and 4β-sulphonamido Analogues of Podophyllotoxin as Potential Antitumor Agents,” Bioorg. & Med. Chem., vol. 11, pp. 5135-5142 (2003). |
| Kamal, A, et al., “A one-pot, efficient and facile synthesis of 4β-arylaminopodophyllotoxins: synthesis of NPF and GL-331 as DNA topoisomerase II inhibitors,” Tetrahedron Lett., vol .44, pp. 8457-8459 (2003). |
| Kamal, A. et al., “Design, synthesis, biological evaluation and QSAR studies of novel bisepipodophyllotoxins as cytotoxic agents,” Bioorganic & Medicinal Chemistry, vol. 12, pp. 4197-4209 (Jun. 2004). |
| Number | Date | Country | |
|---|---|---|---|
| 20110213165 A1 | Sep 2011 | US |
