[Synthesis and antitumor activity of podophyllotoxin derivatives].

According to drug design flattening principle and using podophyllotoxin or 4'-demethylepipodophyllotoxin and aldehydes as starting material,a series of podophyllotoxin derivatives containing an imine structure with low toxicity were highly effective synthesized. Nine target compounds were successfully synthesized,and their structures were confirmed by ~1H-NMR,HR-ESI-MS and melting point data analysis. Using etoposide as positive control drug,nine target compounds were screened for cytotoxicity against He La cells in vitro by MTT method. The antitumor activity screening results showed that compound 6 b,6 d,6 e,6 f,6 g,6 i exhibited higher inhibitory rate against He La cells than those of control drug VP-16. It provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.

[Synthesis and antitumor activity of novel indole podophyllotoxin derivatives].

According to drug design flattening principle,a series of novel indole podophyllotoxin derivatives which were introduced different indole substituents in C-4 position on the basis of podophyllotoxin nucleus were synthesized with the starting material podophyllotoxin and 1 H-indole-5-carboxylic acid. Its anti-tumor activity in vitro was tested in order to screen for high-efficiency and low-toxic compounds. Six target compounds were synthesized,and were confirmed by~1 H-NMR,~(13)C-NMR,HR-ESI-MS and melting point determination analysis. All these target compounds were not reported by previous literature. Using etoposide as positive control drug,all the target compounds were screened for cytotoxicity against He La cells,K562 cells and K562/A02 cell in vitro by MTT method. The antitumor activity screening results showed that compounds 4 b,4 e,4 f exhibited higher inhibitory rate against He La cells and K562 cells than those of control drug VP-16. This route has the advantages on simple operation and reasonable design,provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.

Synthesis and evaluation of novel podophyllotoxin derivatives as potential antitumor agents.

Cancer multidrug resistance (MDR) is a common cause of treatment failure in cancer patients. Increased expression of permeability glycoprotein (P-gp), which is also known as MDR-1, is the main cause of multidrug resistance. Podophyllotoxin derivatives hold great promise in the battle to overcome multidrug resistance, as they can induce cytotoxicity through multiple mechanisms. Here, we synthesized sixteen novel podophyllotoxin derivatives and evaluated their cytotoxicities in human cancer cell lines, HeLa, K562 and K562/A02. Some of these compounds were more potent than etoposide, a clinically relevant inhibitor of DNA repair enzymes. In particular, compound 5p exhibited the most potent activity toward drug-resistant K562/A02 cells, as it robustly inhibited tumor cell proliferation and induced apoptosis. Furthermore, preliminary investigation suggested that 5p inhibited the expression of MDR-1 in K562/A02 cells more effectively than etoposide.

9-[(Furan-2-ylmeth-yl)amino]-5-(3,4,5-trimeth-oxy-phen-yl)-5,5a,8a,9-tetra-hydro-furo[3',4':6,7]naphtho-[2,3-d][1,3]dioxol-6(8H)-one.

In title compound, C(27)H(27)NO(8), the dihydrofuran-2(3H)-one ring and the six-membered ring fused to it both display envelope conformations. The dihedral angle between the benzene ring of the benzo[d][1,3]dioxole group and the other benzene ring is 60.59 (2)°. In the crystal, weak inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into a three-dimensional network. The furan ring is disordered over two sets of sites with occupancies of 0.722 (7) and 0.278 (7).

N-Cyclo-hexyl-2-(5-fluoro-1H-indol-3-yl)-2-oxoacetamide.

In title compound, C(16)H(17)FN(2)O(2), the cyclo-hexane ring adopts a chair conformation.. The crystal packing is stabilized by weak π-π stacking inter-actions [centroid-centroid distance = 3.503 (5) Å] and inter-molecular C-H⋯O, N-H⋯O and N-H⋯F hydrogen-bond inter-actions.

2-(1-Ethyl-5-meth-oxy-1H-indol-3-yl)-N-isopropyl-2-oxoacetamide.

In the title compound, C(16)H(20)N(2)O(3), the crystal packing is stabilized by weak π-π stacking inter-actions [centroid-centroid distances = 3.577 (9) and 3.693 (9) Å] and inter-molecular C-H⋯O and N-H⋯O hydrogen-bond inter-actions. The C atoms of the N-isopropyl group are disordered over two sets of sites with occupancies of 0.61(3) and 0.39(3).

9-{[4-(Dimethyl-amino)-benzyl]amino}-5-(4-hy-droxy-3,5-dimeth-oxy-phenyl)-5,5a,8a,9-tetra-hydro-furo[3',4':6,7]naphtho-[2,3-d][1,3]dioxol-6(8H)-one methanol monosolvate.

In the title compound, C(30)H(32)N(2)O(7)·CH(4)O, the tetra-hydro-furan ring and the six-membered ring fused to it both display envelope conformations, with the ring C atom opposite the carbonyl group and the adjacent bridgehead C atom as the flaps, respectively. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link all moieties into ribbons along [010]. Weak inter-molecular C-H⋯O inter-actions consolidate the crystal packing further.