Search

We describe the screening of a set of cryptopleurine derivatives, namely thienoquinolizidine derivatives and (epi-)benzo analogs with bioactive phenanthroquinolizidine alkaloids that induce cytotoxic effects in the mouse lymphocytic leukemia cell line L1210. We used three variants of L1210 cells: i) parental cells (S) negative for P-glycoprotein (P-gp) expression; ii) P-glycoprotein positive cells (R), obtained by selection with vincristine; iii) P-glycoprotein positive cells (T), obtained by stable transfection with a human gene encoding P-glycoprotein. We identified the most effective derivative 11 with a median lethal concentration of ≈13 μM in all three L1210 cell variants. The analysis of the apoptosis/necrosis induced by derivative 11 revealed that cell death was the result of apoptosis with late apoptosis characteristics. Derivative 11 did not induce a strong alteration in the proportion of cells in the G1, S or G2/M phase of the cell cycle, but a strong increase in the number of S, R and T cells in the subG1 phase was detected. These findings indicated that we identified the most effective inducer of cell death, derivative 11, and this derivative effectively induced cell death in S, R and T cells at similar inhibitory concentrations independent of P-gp expression.

The stereoselective synthesis of epi -thieno analogues of the phenanthroquinolizidine bioactive alkaloids (−)-Cryptopleurine and (−)-(15 R )-Hydroxycryptopleurine was achieved in five steps starting from easily available enantiopure ( S )-2-aminoadipic acid used as chiral pool and nitrogen atom source. During these investigations, both π-cationic cyclization of chiral N -thienylmethyl-6-oxopipecolinic acids into pure ( S )-keto-lactams and theirs regioselective and diastereoselective reduction, considered as key steps of this sequence, were studied. Of particular interest, the Friedel–Crafts cyclization using (CF 3 CO) 2 O/BF 3 ·Et 2 O show that near the expected keto-lactams, enamides and enamidones containing trifluoromethyl residue were isolated. A mechanism leading to the latter products with high synthetic potential was discussed. [ABSTRACT FROM AUTHOR]

A series of 7-methoxycryptopleurine derivatives 2- 23 were prepared and evaluated for their antiviral activity against tobacco mosaic virus ( TMV) for the first time. The bioassay results showed that most of these compounds exhibited excellent in vivo anti- TMV activity, of which 7-methoxycryptopleurine salt derivatives 16, 19, and 23 displayed significantly higher activity than 7-methoxycryptopleurine ( 1) and commercial ribavirin and ningnanmycin. Salification, the most commonly employed method for modifying physical-chemical properties, did significantly increase antiviral activity, and different salt forms displayed different antiviral effect. This study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus. [ABSTRACT FROM AUTHOR]

Abstract: A concise and efficient route involving Parham-type cycliacylation as the key step has been used to synthesize phenanthroquinolizidine alkaloids 1a–c and 2a–c. Among the products, 1b-( S ), 1b-( R ), 2a-(14a S ,15 S ), 2a-(14a R ,15 R ), and 2b were synthesized for the first time. [Copyright &y& Elsevier]

We describe the screening of a set of cryptopleurine derivatives, namely thienoquinolizidine derivatives and (epi-)benzo analogs with bioactive phenanthroquinolizidine alkaloids that induce cytotoxic effects in the mouse lymphocytic leukemia cell line L1210. We used three variants of L1210 cells: i) parental cells (S) negative for P-glycoprotein (P-gp) expression; ii) P-glycoprotein positive cells (R), obtained by selection with vincristine; iii) P-glycoprotein positive cells (T), obtained by stable transfection with a human gene encoding P-glycoprotein. We identified the most effective derivative 11 with a median lethal concentration of ≈13 μM in all three L1210 cell variants. The analysis of the apoptosis/necrosis induced by derivative 11 revealed that cell death was the result of apoptosis with late apoptosis characteristics. Derivative 11 did not induce a strong alteration in the proportion of cells in the G1, S or G2/M phase of the cell cycle, but a strong increase in the number of S, R and T cells in the subG1 phase was detected. These findings indicated that we identified the most effective inducer of cell death, derivative 11, and this derivative effectively induced cell death in S, R and T cells at similar inhibitory concentrations independent of P-gp expression. [ABSTRACT FROM AUTHOR]