Studies on Nicotinoids1) as an Insecticide

Toxicities of some nicotinoids as an insecticide were determined. 5′-methylnornicotine, a new synthetic isomer of nicotine, shows similar toxicity to nicotine. The essential moiety in nicotinoids molecule responsible for high toxicity may be 3-pyridylmethylamine group, the amino nitrogen of which must have high basicity (p^K_a′: 7.4~9.0). All nicotinoids of high toxicity are estimated to be largely as monocation at physiological pH of 7.     

Novel Iron Complexes Behave Like Superoxide Dismutase In Vivo

Novel iron and copper complexes having tris[N-(5-methyl-2-pyridylmethyl)-2-aminoethyl]amine (5MeT-PAA), tris[N-(3-methyl-2-pyridylmethyl)-2-aminoethyl]amine(3MeTPAA),rris[N-(5-methoxycarbonyl-2-pyridylmethyl)-2-aminoethyl]amine (TNAA), tris[(2-thienylmethyI)-2-aminoethyl]amine (TTAA), tris[(2-furylniethyl)-2-aminoethyl]amine (TFAA) or tris[(2-imidazolyl)-2-aminoethyl]amine (TIAA) as ligand. were synthesized to examine the superoxide dismutase (SOD) activity. The concentrations of Fe-3MeTPAA and Fe-TIAA equivalent to 1 unit of SOD (IC₅₀) were 0.5 μM and I.O μM. respectively. Fe-3MeTPAA and Fe-TIAA had higher SOD activity than other Fe and Cu complexes and protected Escherichiu coli cells from paraquat toxicity. In case of using tris[N-(Cmethyl-2-pyridylrnethyl)-2-aminoethyl]amine (6MeTPAA) as ligand, the Fe complex could not be obtained, which may be due to the steric hindrance of Cmethyl substituent. Generally, Cu complexes had low SOD activity, compared with Fe complexes, and could not suppress paraquat toxicity.     

Studies on Nicotinoids as an Insecticide

The inhibition of house fly head Cholinesterase by twelve nicotinoids and twenty six pyridylalkylamines was investigated in relation to their ionizations and toxicities to house flies, Musca domestica L. The significant correlation between toxicity and inhibition, and the competitive nature of inhibition indicate that there are some similarities between the receptor for toxic action and the active center of Cholinesterase for combining the molecule. Cholinesterase inhibition is shown to be caused by the anionic site binding on the enzyme of the cationic head of the molecule. Hence, the toxic action of nicotine and 3-pyridylmethylamines is best explained by postulating the nerve receptor carrying the anionic site, which is partly similar to the anionic site of the active center in cholinesterase. The effect on fly nerve activity can also be correlated with the chemical structure. It is shown that the highly toxic nicotinoids should be provided with high but not too high basicity. Dihydronicotyrine having pKa′ near the pH of insect body fluid shows the highest toxicity. This can be understood in terms of the preference of free base for penetration and the requirement of ionization for the interaction with the receptor.     

Coordination properties of 3′,5′-cyclic adenosine monophosphate towards copper(II) ions

The metal binding ability of 3′,5′-cyclic adenosine monophosphate (3′,5′-cAMP) molecule using copper(II) ion, as an example of biologically available divalent metal ion, was investigated by potentiometry, EPR and differential spectroscopy (UV-Vis, CD). One complex with stoichiometry Cu(3′,5′-cAMP)⁺ was found, where Cu(II) ion is bound by N-7 nitrogen of adenine moiety.     

Some Peculiarities of the Dynamics of the Immunoglobulin M Structure

Abstract

The isotropic mobility of separate regions of the intact molecule of immunoglobulin M (IgM) and its Fab and (Fc)₅ fragments was studied using spin-labeling of carbohydrate (2,2,6,6-tetramethyl-4-aminopiperidine-l-oxyl) and peptide (2,2,5,5-tetramethyl-3-dichloro-triazinylaminopyrrolidine-l-oxyl) moieties.

The spin-labeled oligosaccharide groups (OGs) in the Fab region are shown to have much more amplitude of anisotropic motion than those in the (Fc)₅ region. The spin label in the latter is evidently attached in the Cμ3 domain to one of its OGs which is probably stabilized by ionic contacts between terminal N-acetylneuraminic acid residue and the peptide moiety of the IgM molecule.

When the amount of the glycosidase-cleaved carbohydrate does not exceed 10–15%, most OGs affected are of the Fab region. Upon profound splitting (≥50%) the OGs of the (Fc)₅region are also affected; that results evidently in loosening the ionic contacts between the shortened OGs and the peptide moiety of IgM, and consequently in increasing mobility of the former.

The structure of the (Fc)₅ region of IgM is labile; after detaching this moiety from the intact IgM molecule, its structure is stabilized, but one of its domains (Cμ3) becomes more mobile than it is in the intact IgM molecule; at the same time the amplitude of anisotropic motion of OG bound here is decreased. In the latter case, this decrease depends on the sequence of spin-labeling and fragmentation.

The most probable cause of stabilization of the (Fc)₅ fragment is the heating of IgM solution to 56°C during fragmentation with trypsin. At this temperature the τ value for the (Fc)₅ fragment is unusually low, equaling 23 ns.

The spin-labeling in the peptide part of IgM occurs mostly in the Fab region which is a rather rigid moiety as expected.     

Irreversible,Tight-Binding Inhibition of Adenosine Deaminase by Coformycins: Inhibitor Structural Features That Contribute to the Mode of Enzyme Inhibition

Abstract

Coformycin analogues 1–6 were synthesized and biochemically screened against adenosine deaminase in order to assess the relative contributions of N-4, N-6, and the N-3 sugar moiety to the mode of enzyme inhibition. Our results indicate that N-4 plays a relatively greater role than N-6 in enzyme tight-binding, and that a benzyl group can substitute for the sugar moiety at N-3. The absence of a sugar or benzyl group at N-3, however, leads to loss of activity. The hydroxyl group at C-8, while crucial for activity, does not alone confer the tight-binding characteristics to coformycins.     

Novel Acyclic Analogues of Purine Nucleosides: 2,3-Dihydroxy-1-Methoxypropyl and 3-Hydroxy-1-Methoxypropyl Derivatives

Abstract

Novel purine nucleoside analogues in which the N-9 ribosyl moiety is replaced by a 2,3-dihydroxy-1-methoxypropyl or 3-hydroxy-1-methoxypropyl substituent and their N-7 substituted isomers have been synthesized and tested for antiviral activity.     

Novel Acyclonucleosides. Part 2. 2, 3-Dihydroxy-1-Methoxypropyl-and 3-Hydroxy-1-Methoxypropyl-Substituted Purines

Abstract

Novel purine nucleoside analogues in which the N-9 ribosyl moiety is replaced by a 2,3-dihydroxy-1-methoxypropyl or 3-hydroxy- 1-methoxy-propyl substituent and their N-7 substituted isomers have been synthesized and tested for antiviral activity.     

Different structural requirements of endotoxic glycolipid for tumor regression and endotoxic activity

Endotoxic glycolipid extracted from the heptose-less mutant of $\text{Salmonella typhimurium}$ was treated with alkali and acid reagents. The glycolipid freed of all O-ester linked fatty acids by hydroxylamine had lost tumor regression activity and toxicity, whereas a partial removal of O-ester linked fatty acids by mild alkali did not impair with these activities. The glycolipid retained both activities after removal of 2-keto-3-deoxyotonate by sodium acetate (pH 4.5) but was rendered nontoxic while retaining antitumor activity when hydrolyzed by 0.1N HCl whereby 2-keto-3-deoxyoctonate and glycosidic phosphate was split off the glycolipid molecule. Nontoxic and tumor regressive fractions were separated by means of preparative thin layer chromatography of glycolipid hydrolyzed by mild acid. Thus, it was concluded that glycosidic bound phosphate and at least a portion of fatty acids of the lipid A moiety were essential for toxicity, but that this phosphate is not essential for tumor regression activity.     

Substituent — Directed Aralkylation and Alkylation Reactions of the Tricyclic Analogues of Acyclovir and Guanosine

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine (6-R-TACV)¹ 1 partly directs aralkylation reactions into unusual positions: N-4 to give 3 and C-7 to give N-5, 7-disubstituted or N-4, 7-disubstituted derivatives. In the case of alkylation the effect is limited to aryl substituent and position N-4. Replacement of acyclic moiety of 1 with a ribosyl one like in 7 prevents N-4 substitution. Cleavage of the third ring of 3b to give 3-benzylacyclovir 10 is an example of a new short route to 3-aralkyl-9-substituted guanines.     

Novel Acyclic Analogues of Pyrimidine Nucleosides: 1-Methoxy-2, 3-Dihydroxypropyl and 1-Methoxy-3-hydroxypropyl Derivatives

Abstract

The preparation of a series of novel pyrimidine nucleoside analogues in which the N-1 ribosyl moiety is replaced by 1-methoxy-2, 3-dihydroxypropyl and 1-methoxy-3-hydroxypropyl substituents is described.     

Synthesis, structure and properties of bis[N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamidecopper(II)] perchlorate

In this account we report the synthesis, structure and characterization of a dimeric Cu(II) complex, [Cu₂(PaPy₃H)₂](ClO₄)₄ (bis[N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamidecopper(II)]). In this complex, the coordination of the designed ligand PaPy₃H to the Cu(II) centers is completed by the bis(picolyl)methyl amine portion of one PaPy₃H unit and the oxygen and pyridine nitrogen atoms of the pyridine-2-carboxamide moiety of a second PaPy₃H ligand. The resulting dimeric complex demonstrates a new mode of coordination of the ligand PaPy₃H.     

Novel Acyclonucleosides. Part I. 2,3-Dihydroxy-1-Methoxypropyl-and 3-Hydroxy-1-Methoxypropyl-Substituted Pyrimidines

Abstract

Novel pyrimidine nucleoside analogues in which the N-1 ribosyl moiety is replaced by a 2,3-dihydroxy-1-methoxypropyl or 3-hydroxy-1-methoxypropyl substituent have been synthesized and tested for antiviral activity.     

The Novel 6–(N-Pyrrolyl)purine Acyclic Nucleosides: 1H and 13C NMR and X-ray Structural Study†

Abstract

Synthesis of the novel nucleoside analogues containing exocyclic pyrrolo moiety and acyclic side chains attached to the purine ring at N-9 and N-7 is described. The site of alkylation was determined by ¹H and ¹³C NMR on the basis of chemical shifts, C-H coupling constants and connectivity in NOESY and HETCOR spectra. The N-9 substitution of 7 was proved by its X-ray crystallographic analysis.

     

Intramolecular ether oxygen coordination in the zinc complexes with dipicolylamine (DPA)-derived ligands

The ether oxygen coordination to the zinc center in the complexes with dipicolylamine (DPA)-derived ligands, N-(2-methoxyethyl)-N,N-bis(2-pyridylmethyl)amine (L), N-(3-methoxypropyl)-N,N-bis(2-pyridylmethyl)amine (L′), and N-{3-(2-pyridylmethyloxy)propyl}-N,N-bis(2-pyridylmethyl)amine (L^Py) has been discussed. Upon chelation of the oxygen atom, L forms a five-membered chelate ring with respect to the 2-aminoethyl ether moiety whereas L′ forms a six-membered chelate in 3-aminopropyl ether unit. This difference was highlighted by the crystal structures of ZnCl₂ complexes, in which [Zn(L)Cl₂] (1) exhibited ether oxygen coordination but [Zn(L′)Cl₂] (2) had the ether oxygen non-coordinated. The terminal pyridyl group of L^Py facilitates the ether oxygen atom coordination via a metal binding from the basal plane trans to the aliphatic nitrogen.     

Double-sides sticking mechanism of vinblastine interacting with α,β-tubulin to get activity against cancer cells

Abstract

Vinblastine (VLB) and its derivatives have been used for clinical first-line drugs to treat various cancers. Due to the resistance and serious side effects from using VLB and its derivatives, there is a need to discover and develop novel VLB derivatives with high activity against cancer cells. In order to better discover and develop new VLB derivatives, we need to study the structural basis of VLB's anti-cancer cytotoxicity and the mechanism of its interaction with α,β-tubulins. Based on the crystal structure of α,β-microtubule complex protein, the molecular dynamics method including the sampling PMF method was used to study the variation of dissociation free energy (ΔG) of α,β-tubulins under different system conditions, and then from which to study the mechanism of the interaction between VLB and α,β-tubulins. The obtained results show that the dissociation of pure α,β-tubulins requires 197.8?kJ·mol^?1 for ΔG. When the VLB molecule exists between the interface of α,β-tubulins, the dissociation ΔG of α,β-tubulins reaches 220.5?kJ·mol^?1, which is greater than that of pure α,β-tubulin. The VLB molecule is formed by connecting a vindoline moiety (VM) molecule with a catharanthine moiety (CM) molecule through a carbon-carbon bond, which is a larger molecule. When the CM molecule exists in the middle of α,β-tubulin interface, the dissociation ΔG of α,β-tubulins is 46.2?kJ·mol^?1, during which the CM moves with β-tubulin. When the VM molecule exists between the middle of α,β-tubulin interface, the dissociation ΔG of α,β-tubulins is 86.7?kJ·mol^?1, during which it moves with α-tubulin. Therefore, the VLB molecule is like a double-sides tape to stick α-tubulin and β-tubulin together. The VLB molecule intervenes the dynamic equilibrium between dissociation and aggregation of α-tubulin and β-tubulin by a double-sides sticking mechanism to exert high activity with toxicity against cancer cell. Besides, our results demonstrate that VLB has its structural basis for anticancer cytotoxicity due to its two compositions composed of a CM molecule and a VM molecule although they have little toxicity against cancer cell alone.     

Synthesis and anti-HIV evaluation of new 2′,3′- dideoxy-3′-thiacytidine prodrugs

Abstract

A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2′,3′-dideoxy-3′-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2′,3′-dideoxy-3′-thiacytidine prodrugs which differ from each other by the length, the nature of the 5′-O function and the 5′-O or /and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations ECso of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed.     

Dinuclear oxovanadium(IV) compounds from designed amino acid derivatives

Two dinuclear oxovanadium(IV) compounds [V(O)(NMet)(μ-OMe)]₂ · MeOH (1) and [V(O)(NThr)(μ-OMe)]₂ · MeOH (2) were prepared by the reaction of VOSO₄ and ONN donor ligands, HNMet and HNThr (HNMet =N-(2-pyridylmethyl)-dl-methionine, HNThr = N-(2-pyridylmethyl)-dl-threonine) derived from 2-pyridinecarbaldehyde and dl-methionine/dl-threonine. Both of these compounds are characterized by single crystal X-ray diffraction. X-ray crystallography revealed that the two vanadium(IV) compounds are both dinuclear structures bridged by methanol groups. Each vanadium atom is six coordinated in a distorted octahedral environment. IR spectroscopy and EPR spectra for these two compounds are also given.     

Protease Inhibitors. Part 2. Weakly Basic Thrombin Inhibitors Incorporating Sulfonyl-Aminoguanidine Moieties as S1 Anchoring Groups: Synthesis and Structure-Activity Correlations

Abstract

Two series of derivatives have been prepared and assayed as inhibitors of two physiologically relevant serine proteases, human thrombin and human trypsin. The first series includes alkyl-/ aralkyl-/aryl- and hetarylsulfonyl-aminoguanidines. It was thus observed that sulfanilyl-aminoguanidine possesses moderate but intrinsically selective thrombin inhibitory properties, with K_i values around 90 and 1400 nM against thrombin and trypsin respectively. Further elaboration of this molecule afforded compounds that inhibited thrombin with K_i values in the range 10–50 nM, whereas affinity for trypsin remained relatively low. Such compounds were obtained either by attaching benzyloxycarbonyl- or 4-toluenesulfonylureido-protected amino acids (such as D-Phe, L-Pro) or dipeptides (such as Phe-Pro, Gly-His, β-Ala-His or Pro-Gly) to the N-4 atom of the lead molecule, sulfanilyl-aminoguanidine, or by attaching substituted-pyridinium-propylcarboxamido moieties to this lead. Thus, this study brings novel insights regarding a novel non-basic S1 anchoring moiety (i, e., SO₂NHNHC(=NH)NH₂), and new types of peptidomimetic scaffolds obtained by incorporating tosylureido-amino acids/pyridinium-substituted-GABA moieties in the hydrophobic binding site(s). Structure-activity correlations of the new serine protease inhibitors are also discussed based on a QSAR model described previously for a large series of structurally-related derivatives (Supuran et al. (1999) J. Med. Chem., in press).     

Structure Modifications of S-n-Butyl S′-p-tert-Butylbenzyl N-3-Pyridyldithiocarbonimidate (S–1358, Denmert®) and Fungicidal Activities

Since S-n-butyl S′-p-tert-butylbenzyl N-3-pyridyldithiocarbonimidate, a potent fungicide to powdery mildew, is known to inhibit ergosterol biosynthesis in Monilinia fructigena, the activities were assessed on 24 compounds having other substituents than the 3-pyridyl and on 24 compounds having a variety of different structures connecting the 3-pyridyl and the p-tert-butylphenyl group from that of the dithiocarbonimidate.

In the former group the 3-pyridyl group was essential for the activities and the substitution at the 2- or 6-position resulted, on available data, in inactive compounds. Several other β-N-heterocyclic analogs were also active. In the latter group, a number of modified compounds from the dithiocarbonimidate structure were shown to be active.