Anticancer drug design based on plant-derived natural products

This review article focuses on recent research in my laboratory on various classes of compounds that possess potent antitumor activity. These compounds were obtained by bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design-based modification and analog synthesis. Structural modification, structure-activity relationship, and mechanism of action studies will be discussed.Antitumor Agents 195 [for part 194, see ref. 68].     

Passive avoidance behavior: Opposite effects of oxytocin analogs with agonist and antagonist properties

Deamino-6-carba-oxytoxin (dC6O), a potent oxytocin analog considered to be resistant to some of the physiologically significant enzymic systems, and $\text{N-α-}\text{acetyl}\text{-[2-O-}\text{methyltyrosine}\text{]}\text{oxytocin}$ (AMTO), an analog acting as a competitive inhibitor of oxytocin on the rat uterus, were studied in rats trained in a passive avoidance task.Subcutanaeous administartion of dC6O (5–50 gmg·kg^?1) during different phases of the passive avoidance learning paradigm attenuated avoidance latencies; the results indicated that the drug induced state-dependent learning.AMTO (5–20 gmg·kg^?1) enhanced avoidance latencies when administered subcutaneously before training trials and/or before retention test trials. This effect occured in both males and females. The analogs did not influence exploratory behavior in open field.The results suggest that oxytoxin, in contrast to vasopressin, may impair memory processes. However, both analogs failed to influence the passive avoidance response when administered after training. This finding indicates that dC6O and AMTO did not influence the mechanism of memory consolidation whereas vasopressin and oxytoxin had a marked effect.     

Synthesis and sst(2) binding profiles of new [Tyr(3)]octreotate analogs.

One of the main objectives of our current work is the development of new somatostatin analogs that would retain the general characteristics of [Tyr(3)]octreotate (Tate) while showing potential for clinical application. In this respect, study of their interaction with the sst(2) is crucial in providing preliminary structure-activity relationships data. In the present work we report on the synthesis and the preliminary biological evaluation of a total of 15 new structurally modified [Tyr(3)]octreotate analogs. The binding affinities were determined during competition binding assays in sst(2)-positive rat acinar pancreatic AR4-2J cell membranes using [(125)I-Tyr(3)]octreotide as the radioligand.     

Iron complexes of chiral phenol-oxazoline ligands: Structural studies and oxidation catalysis

Iron complexes of two ligands, HphoxCOOH and HphoxiPr, have been synthesized and characterized by crystal structure analyses. The complexes (HNEt₃)₂[Fe(phoxCOO)₂](ClO₄) and [Fe(phoxiPr)₃] are reported. Reactions of the ligands rac-HphoxCOOH and rac-HphoxiPr with iron(II) or iron(III) perchlorate result in the formation of iron(III) complexes with pseudo-octahedral geometry around the metal center. The iron complex obtained from rac-HphoxCOOH crystallized in the centrosymmetric space group Cmca. The two ligands are bound in a tridentate manner generating a meridional coordination with both dianionic ligands on a metal center having the same chirality; due to the center of symmetry the complex with opposite chirality is also present. The complex (HNEt₃)₂[Fe(phoxCOO)₂](ClO₄) is the first accurate structural model of the iron complex of a siderophore analog commonly observed in mycobactins. The three didentate ligands in the complex [Fe(phoxiPr)₃] are bound with like atoms in a meridional manner to the metal center. The metal ion is surrounded by two ligands of the same chirality and one ligand of opposite chirality (ie. RRS or SSR); due to the presence of a center of symmetry both isomers are present in the crystal structure. The complex (HNEt₃)₂[Fe(phoxCOO)₂](ClO₄) shows promising activity in the oxidation of alkanes, such as toluene, ethylbenzene and cumene, while the complex [Fe(phoxiPr)₃] does not show any catalytic activity in alkane oxidations under the conditions tested. The complex (HNEt₃)₂[Fe(phoxCOO)₂](ClO₄) is reasonably efficient in the conversion of H₂O₂ to oxidation products.     

Bacteriorhodopsins containing modified chromophores: A study on the wild type and D96N mutant of Halobacterium salinarum

Modification of the chromophore in bacteriorhodopsin (BR) from ET1001 and D96N strains of Halobacterium salinarum (halobium) was carried out. Purple membranes were decolored by means of light-dependent hydroxylaminolysis. The all-trans -isomers of retinal and its 3,4-didehydro-, 4-keto-, and phenyl analogs were reconstituted into apomembranes. Absorption maxima of the homonymic pigments in both strains were similar. The kinetics of the M-intermediates in the mode of a single turnover of the photocycle induced by a short light flash (532 nm, 15 ns) was compared. For the investigated bacteriorhodopsin analogs the efficiency of the M-intermediate formation did not exhibit any reliable dependence on the point mutation. Both for ET1001 and for D96N strains the M-relaxation of the 4-ketoBR was distinctly biphasic, with the slow phase comprising about 10–15% of the signal amplitude. Replacement of the ionone ring by phenyl caused a weak deceleration of the M relaxation (～1.5-fold decrease in t _1/2). Independence of the photocycle deceleration of the point mutation and chromophore modification was shown for all BR analogs studied.     

Effect of antibiotics on ethylene production by soil micro-organisms

Summary Treatment of arable soils with antibacterial (novobiocin) and antifungal (cycloheximide) agents had no effect on ethylene accumulation. Novobiocin had a very small effect on the growth ofMucor hiemalis and cycloheximide decreased its maximum specific growth rate but neither agent impaired the capacity of the fungal culture to produce ethylene. Caution must therefore be exercised when using antibiotics to establish the source of soil metabolic processes.     

Drosophila melanogaster deoxyribonucleoside kinase activates gemcitabine

Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK) can additionally sensitize human cancer cell lines towards the anti-cancer drug gemcitabine. We show that this property is based on the Dm-dNK ability to efficiently phosphorylate gemcitabine. The 2.2 Å resolution structure of Dm-dNK in complex with gemcitabine shows that the residues Tyr70 and Arg105 play a crucial role in the firm positioning of gemcitabine by extra interactions made by the fluoride atoms. This explains why gemcitabine is a good substrate for Dm-dNK.