ABSTRACT
A total synthesis of (+)-quassin from naturally occurring (S)-(+)-carvone is described. The total number of steps was 28, and the overall yield was about 2.6%. The synthetic strategy for the construction of the tetracyclic carbon framework was based on a C-->ABC-->ABCD ring annulation sequence, involving an aldol reaction, an intramolecular Diels-Alder reaction, and an intramolecular acylation as the key steps. Subsequent functionalization of ring A and ring C then afforded the target (+)-quassin.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Glaucarubin/analogs & derivatives , Quassins , Glaucarubin/chemical synthesis , Indicators and Reagents , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
The (1R,6S)- and (1R,2S,6S)-diastereoisomers of cyclophellitol were found to be effective irreversible inactivators of alpha-D-glucosidase and alpha-D-mannosidase, respectively. The (1R,6S)-diastereoisomer inactivates brewers yeast alpha-D-glucosidase according to pseudo-first order kinetics with inactivation constants of Ki = 26.9 microM, ki = 0.401 min-1 while the (1R,2S,6S)-diastereoisomer inactivates jack beans alpha-D-mannosidase in a similar manner with Ki = 120 microM, ki = 2.85 min-1. The irreversibility of these compounds was evidenced by the lack of reactivation upon dialysis of the inactivated enzyme.
Subject(s)
Cyclohexanols/chemistry , Cyclohexanols/pharmacology , Glycoside Hydrolase Inhibitors , Mannosidases/antagonists & inhibitors , Kinetics , Saccharomyces cerevisiae/enzymology , Stereoisomerism , Structure-Activity Relationship , alpha-Mannosidase , beta-Glucosidase/antagonists & inhibitorsABSTRACT
Chemically synthesized (+)-goniopypyrone was found to suppress the growth of cultured Ehrlich ascites tumor cells as well as PU5-1.8 cells. The ED50 values were found to be 35 and 30 micrograms/ml for the two cell lines used. An LD50 of 193 micrograms/ml was observed in the brine shrimp bioassay.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Ehrlich Tumor/drug therapy , Lactones/pharmacology , Styrenes/pharmacology , Animals , Cell Line , Humans , Lactones/chemical synthesis , Styrenes/chemical synthesis , Tumor Cells, Cultured/drug effectsABSTRACT
Syntheses are described for and structure:activity studies undertaken of the anti-tumour activity of (2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-+ ++enone) (1) and its analogues 1-crotonyloxymethyl-(3R,4S,5R)-3,4,5-trihydroxycyclohex-1-en e (3), 1-crotonyloxymethyl-(3R,4S,5S)-3,4,5-trihydroxycyclohexene (4) and 2-crotonyloxymethyl-2-cyclohexenone (5), which differ from 1 in the presence/absence of the cyclic keto group and/or the stereochemistry at one of the -OH bearing carbon atoms. None of the above compounds, including 1, directly inhibited glyoxalase I, isolated for the first time to homogeneity from rat Yoshida sarcomas and for which a purification protocol was developed. The apparent inhibition of glyoxalase I by 1 and 5 (but not detected for 4 or 3) could be explained by reaction of 1 and 5 with the glutathione present in the assay buffer and the consequent depletion of substrate. 1 and 5 were found to react readily with glutathione whereas 4 and 3 did not react. In vitro chemosensitivity studies against a panel of tumour cell lines of both mouse and human origin showed that in parallel with their thiol reactivity, 1 and 5 exhibited significant in vitro cytotoxicity whereas 4 and 3 did not. Concentrations of drug required to cause 50% cell kill (ID50 values) were in the range 0.5-19 microM (0.1-2.8 micrograms/ml) for 5, and 3-44 microM (0.7-10 micrograms/ml) for 1. The structural features causing the differences in antitumour effects were localized on this basis to the alpha,beta-unsaturated ketone linkage as opposed to the stereochemistry of the (trihydroxy) alcoholic sites.