Synthesis, DNA intercalation and 3D QSAR analysis of cis-2,4,5-trisubstituted-1,3-dithiolanes as a novel class of antitumor agents.

Acid-catalyzed transacetalation of dimethyl (2R,3S)-2,3-dimercapto-succinate and 1,1,3,3-tetramethoxypropane provided cis-4,5-dimethoxycarbonyl-2-(2',2'-dimethoxyethyl)-1,3-dithiolane (2) in 77% yield. The esterification of 2 and l-amino acids provided 18 active antitumor cis-2-carbonylmethyl-4,5- di(l-aminoacyloxymethyl)-1,3-dithiolane analogs (5a-r). Five compounds (5b,c,e,k,p) exhibited remarkable antitumor activity in in vivo assays. The in vivo antitumor potency of 5e,k,p at 44.64micromol/kg was similar to that of cytarabine at 89.28micromol/kg. Several different assay systems, including UV-vis of CT DNA with or without the representative compound 5d and CD spectra of CT DNA with or without representative compounds 5b,f,i demonstrated that DNA is the target of 5a-r. A 3D QSAR model was established to elucidate quantitative relationships between in vivo antitumor activity and analog structures. An equation with r(2) equal to 0.992 was built to predict antitumor activity of unknown cis-2,4,5-trisubstituted-1,3-dithiolane analogs.

Suppression of respiratory burst in human neutrophils by new synthetic pyrrolo-benzylisoquinolines.

Reactive oxygen species produced by neutrophils contribute to the pathogenesis of inflammatory diseases. In this study, the inhibition of superoxide anion (O2*-) generation in human neutrophils by new synthetic pyrrolo-benzylisoquinoline derivatives was determined. We found that KW-2, KW-5, and KW-7 (8,9-dimethoxyl-1-(R-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-2,3-dione; where R is 3-chloro, 3-bromo, and 4-methoxy, respectively) were the most effective inhibitors of formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced O2*- release in human neutrophils. KW-2, KW-5, and KW-7 displayed no antioxidant or O2*--scavenging ability. The inhibition of O2*- generation was reversed by the protein kinase (PK)A inhibitor, N-(2-((p-bromocinnamyl)amino)ethyl)-5-isoquinolinesulfonamide (H89), but not by the PKG inhibitor (8R,9S,11S)-(-)-2-methyl-9-methoxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclocta(cde)trinen-1-one (KT5823), or the soluble guanylate cyclase (sGC) inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). KW derivatives increased cellular cyclic AMP concentrations through the inhibition of phosphodiesterase (PDE) activity but not the elevation of adenylate cyclase (AC) activity. These results indicate that inhibition of FMLP-induced respiratory burst in human neutrophils by KW derivatives are cyclic AMP/PKA-dependent and are due to inhibition of PDE. The new chemical skeleton of PDE inhibitors may protect against the progression of inflammation.

Antiplatelet effects of KW-7, a new inhibitor of cyclic nucleotide phosphodiesterases.

The antiplatelet effect of a new synthetic compound, 8,9-dimethoxyl-1-(4-methoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-2,3-dione (KW-7), was determined in rabbit platelets. KW-7 concentration-dependently prevented platelet aggregation caused by arachidonic acid, collagen, platelet-activating factor, and thrombin. KW-7 induced a substantial increase in cyclic AMP levels and a smaller increase in cyclic GMP levels in platelets. In platelet homogenates, KW-7 inhibited both cyclic AMP- and cyclic GMP-phosphodiesterase activities. The antiplatelet effect of KW-7 was reversed by SQ22536 (an inhibitor of adenylate cyclase) and H89 (an inhibitor of protein kinase A) but not by ODQ (an inhibitor of soluble guanylate cyclase). These data suggest that the antiplatelet effect of KW-7 is cyclic AMP-dependent, and is through inhibition of platelet phosphodiesterases. In addition, KW-7 inhibited arachidonic acid-stimulated thromboxane production; this effect was associated with an increase in prostaglandin D(2) levels indicating KW-7 is also an inhibitor of thromboxane synthase. The dual inhibition of KW-7 on phosphodiesterase and thromboxane synthase might provide an attractive target in developing antiplatelet drugs.

Effect of active synthetic 2-substituted quinazolinones on anti-platelet aggregation and the inhibition of superoxide anion generation by neutrophils.

Quinazolinones, 2-substituted and 3-substituted, mainly synthesized by microwave irradiation, were subjected to anti-platelet aggregation and inhibition of superoxide anion generation assays. Interestingly, 2-phenyl-4-quinazolinone (4) exhibited significant inhibitory activities toward platelet aggregation and neutrophil activation, and it might therefore serve as a prototype lead compound.

Antiplatelet activity of benzylisoquinoline derivatives oxidized by cerium(IV) ammonium nitrate.

Oxidation of 1-benzyl-3,4-dihydroisoquinolines with cerium(IV) ammonium nitrate (CAN) under mild condition yielded the mixture of corresponding 1-benzylisoquinolines (b-type) and 1-benzoylisoquinolines (a- or c-type) in an equal yields. The selective oxidation products (c-type) can be prepared by using MeCN instead of MeOH. In the antiplatelet assays, four inducers were employed, including AA, Col, PAF, and Thr. In the PAF or Col induced platelet aggregation, compounds belonging to a- and b-type showed stronger inhibitory effects than aspirin.

Antiplatelet activity of synthetic pyrrolo-benzylisoquinolines.

Pyrrolo-benzylisoquinolines were prepared as target compounds and their antiplatelet aggregation activity, adreno-receptor affinity, and cytotoxicity were screened. Compounds 1d-9d showed specific antiplatelet aggregation activity induced by arachidonic acid and collagen. Among them, 8d and 9d exhibited better activity than the reference drug, aspirin and 9d also showed inhibition of platelet aggregation by all four inducers.

Cytotoxic constituents of the stem bark of Neolitsea acuminatissima.

Three new eudesmanolide sesquiterpenes, neolitacumone A-C (1-3), and one new benzylisoquinoline alkaloid, neolitacumonine (5), along with 27 known compounds were isolated from the stem bark of Neolitsea acuminatissima. The structures of compounds 1-3 and 5 were established on the basis of spectral and chemical evidence. Compounds 2, 3, and 20 were selectively inhibitory to Hep 2,2,15 cells with IC50 values in the range 0.24-0.04 microg/mL. Compound 20 was marginally cytotoxic to Hep G2 cells.