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PubMed2006

The cyclotides and related macrocyclic peptides as scaffolds in drug design.

The applicability of linear peptides as drugs is potentially limited by their susceptibility to proteolytic cleavage and poor bioavailability. Cyclotides are macrocyclic cystine-knotted mini-proteins that have a broad range of bioactivities and are exceptionally stable, being resistant to chemical, thermal and enzymatic degradation. The general limitations of peptides as drugs can potentially be overcome by using the cyclotide framework as a scaffold onto which new activities may be engineered. The potential use of cyclotides and related peptide scaffolds for drug design is evaluated herein, with reference to increasing knowledge of the structures and sequence diversity of natural cyclotides and the emergence of new approaches in protein engineering.

Amino Acid Sequence↗
PubMed1991

Interaction and cleavage of DNA with metal complexes of macrocyclic compound consisting of two 1, 10-phenanthroline.

We have synthesized two metal complexes of the macrocyclic compound (III, IV), with which either Cu2+ or Ru2+ is coordinated, consisting of two 1,10-phenanthroline molecules bridged by sulfur. Interaction of the metal complexes with DNA was examined by spectroscopic method and their binding constants were determined. The DNA cleaving activities of these complexes were also investigated.

Copper↗
PubMed1990

Yttrium-90-labeled monoclonal antibody for therapy: labeling by a new macrocyclic bifunctional chelating agent.

Yttrium-90 (90Y) is a promising radiometal for therapy of cancer due to its high-energy beta emission and a physical half-life of 2.67 days. Bifunctional chelating agents based on DTPA cyclic anhydride or EDTA do not form Y(III) complexes that are stable under physiologic conditions. A new macrocyclic bifunctional chelating agent based on 1,4,7,10-tetraazacylododecane-N,N',N",N"'-tetraacetic acid (DOTA) forms a stable Y(III) complex. It was converted to p-bromoacetamidobenzyl-DOTA (BAD), and conjugated to monoclonal antibody Lym-1 via 2-iminothiolane, either as the free ligand or as the 88Y chelate. Stability studies of Lym-1-2IT-BAD-88Y in human serum in vitro showed no measurable loss of Y(III) from the ligand over a 25-day period. In Raji-tumored mice, tumor uptake was 16.8% of the injected dose per gram of tissue on Day 3. The bone uptake was 2.0, 3.6, and 2.1% injected dose per gram of tissue on Day 1, 3, and 5, respectively. The biodistribution of the control 88Y-citrate demonstrated continuous increase in bone uptake from 13.8% injected dose per gram on Day 1 to 24.9% injected dose per gram on Day 4.

Animals↗
PubMed1990

Macrocyclic chelates of radiometals for diagnosis and therapy.

Monoclonal antibody technology allows the specificity of an antibody for its antigen to be used in targeting cancer cells. Stable attachment of metal ions to antibodies by means of 'bifunctional' chelating agents can add the nuclear, physical and chemical properties of the metallic elements to these target-selective proteins. The conjugation of metals--particularly radionuclides--to monoclonal antibodies results in agents for radioimmunotherapy and other medical applications. Chelators that can hold radiometals with high stability under physiological conditions are essential to avoid excessive radiation damage to non-target cells. Derivatives of polyazamacrocycles (bearing a C-substituted functional group for antibody attachment) can exhibit remarkable kinetic inertness. We have developed a new synthetic route these macrocycles via peptide synthesis and intramolecular tosylamide ring closure. Incubation of the yttrium complex of 2-p-nitrobenzyl-1,4,7,10-tetraazacyclododecane-N,N1N",N'"-te traacetic acid (nitrobenzyl-DOTA) for 18 days in serum results in loss of so little yttrium from the complex (less than 0.5%) that the rate of loss cannot be measured under these conditions. In animal models, conjugates of this chelate with monoclonal antibodies show much lower levels of yttrium in the bone than are found with DTPA chelates prepared from the cyclic anhydride. The rates of loss of indium and cobalt from nitrobenzyl-DOTA in serum are slower than from previously studied chelates. Preliminary clinical imaging studies of 111In-labeled monoclonal antibody conjugates of DOTA show highly encouraging results.

Antibodies, Monoclonal↗
PubMed1989

Critical and controlled tests of activity of a macrocyclic lactone (compound F28249-alpha) against natural infections in internal parasites of equids.

Thirteen critical tests (n = 11 horses and 2 ponies) and 4 controlled tests (n = 4 donkeys and 6 horses) were performed to evaluate the activity of the experimental macrocyclic lactone compound F28249-alpha against internal parasites of equids. In the critical tests, activity was determined mainly against the large parasites, but 1 critical test also included benzimidazole-resistant small strongyles. In the controlled tests, evaluation of drug activity included large parasites and stomach worms in all 4 tests, and lungworms in 2 tests. The period between treatment and euthanasia was 6 to 9 days for the critical tests and 14, 17, or 52 days for the controlled tests. The compound was administered by stomach tube at dose rates of 1, 2, 3, 3.5, or 4 mg/kg of body weight. In the critical tests, removal at all 5 dose rates was 100% for Gasterophilus nasalis (2nd and 3rd instars), Parascaris equorum (mature), Strongylus vulgaris, and Strongulus edentatus from the gastrointestinal tract. For Gasterophilus intestinalis in the stomach, mean removals of 2nd instars were 88% at the rate of 2 mg/kg and 93% to 100% at rates greater than or equal to 3 mg/kg. For 3rd instars, mean removals were 7% at 1 mg/kg, 77% at 2 mg/kg, 90% at 3 mg/kg, and 98% at 3.5 mg/kg. Discharge of G intestinalis in feces was typically a slow, prolonged process and probably higher removal values, especially at lower dose rates, would have attended a longer interval after treatment before necropsy examination.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Muscles↗
PubMedDate not supplied

[Biosynthesis of 14C-macrocyclic trichothecenes].

Possibility of producing (14C)-macrocyclic trichothecenes (MCTC) with high specific activity was studied. (1-14C)-glucose, (2-14C)-acetate and (2-14C)-mevalonate were used as precursors. The best results were obtained when labeled acetate was introduced into the medium at the end of the logarithmic growth stage of Dendrodochium toxicum 5800, a fungus-producer. Individual (14C)-MCTC with high specific activity are obtained: verrucarine A-158.1 microC/mM, rhoridine A-167.4 microC/mM; rhoridine H-161.9 microC/mM.

Chemical Phenomena↗
PubMed1986

Rhizoxin, a macrocyclic lactone antibiotic, as a new antitumor agent against human and murine tumor cells and their vincristine-resistant sublines.

Rhizoxin, isolated from a plant pathogenic fungus which causes rice seedling blight, inhibits the mitosis of the tumor cells in a manner similar to that of Vinca alkaloids as revealed by morphological study and flow cytometry analysis. This new 16-membered macrocyclic lactone showed similar chemotherapeutic effects to those of vincristine against L1210 and P388 leukemia-bearing mice. The drug is also effective against B16 melanoma inoculated i.p. or s.c. Rhizoxin, in contrast to the ansamacrolide, maytansine, was effective against human and murine tumor cells resistant to vincristine and Adriamycin in vitro and in vivo. A maximum 60% increase in life span was obtained in mice inoculated with P388 leukemia resistant to vincristine. Rhizoxin showed greater cytotoxicity in cultured tumor cells than did vincristine. Rhizoxin seems to bear consideration for further development as a new chemotherapeutic agent.

Animals↗
PubMed1984

[Effect of the macrocyclic polyether 15-crown-5 on the ionic permeability of excitable membranes].

The macrocyclic polyether 15-crown-5 at a concentration of 5 . 10(-5)-10(-3) M reduced the frequency of the contractions of an isolated rat auricle, increasing the refractory period of the contractions. The polyether lowered the rate of activation of the slow input current of rat spinal ganglionic neurons and blocked the sodium channels of the electroexcitable membrane without disturbing the function of activation and inactivation mechanisms. The compound under study considerably delayed the onset of and decelerated reactivation of the sodium input current. These actions were calcium-dependent, becoming more demonstrable with reduction of Ca2+ concentration outside the cell. 15-Crown-5 interfered with the action of Ca2+ on the lipid bilayer membrane potential. It is assumed that all the effects described are determined by the formation of 15-crown-5-Ca2+ complexes, thereby leading to the impairment of the packing of the membrane lipoprotein matrix.

Animals↗
PubMedDate not supplied

[Effect of macrocyclic esters on mitochondrial and phosphatidylcholine membranes].

It has been found that some macrocyclic esters have no ionophoric properties, but can block valinomycin-induced potassium transport in mitochondrial membranes and lessen the potassium current induced by valinomycin in phosphatidylcholine bilayers. It has been also discovered that 36-member cyclic esters of succinic acid and propylene glycoles decrease fluorescence of puridine nucleotides in mitochondria and produce a modifying effect on bimolecular phosphatidylcholine membranes in the medium of litium, calcium and magnesium chlorides at unilateral injection. The results obtained suggest that cyclopolyesters under investigation form mixed complexes with the macromolecules in the composition of mitochondrial and phosphatidylcholine membranes with the participation of the integrated ion.

Animals↗
PubMedDate not supplied

[Effect of macrocyclic amidoesters on membranes].

A comparative analysis of new macrocyclic amidoesters effect on the bimolecular lipid membrane as well as on the electroexcitable membrane of snail isolated neurons was carried out. It was shown that the investigated complexes inducing a small change in lipid bilayer conductivity and some changes in Na-Ca neuron current characteristics produce essential changes of rapid potassium as well as late potassium current properties. It was concluded on the basis of these results and potassium compounds specificity that the investigated complexes interact directly with neuron potassium channels.

Amides↗
PubMed1993

Modulation of the activity of a human granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein (pIXY 321) by the macrocyclic lactone protein kinase C activator bryostatin 1.

We have examined the effect of the macrocyclic lactone protein kinase C (PK-C) activator bryostatin 1 on the proliferative capacity and lineage commitment of CD34+ human bone marrow cells exposed to the granulocyte-macrophage colony-stimulating factor/interleukin-3 (GM-CSF/IL-3) fusion protein pIXY 321. pIXY 321 administered at a dose of 10 ng/mL was as effective as the combination of plateau concentrations of recombinant (r) IL-3 and rGM-CSF (e.g., 50 ng/mL) in stimulating the growth of day-14 committed myeloid progenitors (colony-forming units granulocyte/macrophage [CFU-GM]). In the large majority of samples tested, coadministration of 0.5 to 100 nM bryostatin 1 with either pIXY 321 or the combination of rIL-3 plus rGM-CSF led to modest but significant increases (e.g., 30 to 75%) in the number of CFU-GM, compared to administration of growth factors alone. The degree of bryostatin 1-induced potentiation, however, was considerably less than that previously observed in the case of cells exposed to either rIL-3 or rGM-CSF, where increases of 100 to 150% were regularly noted. While at least 50% of day-14 CFU-GM stimulated by either pIXY 321 or the combination of rIL-3 plus rGM-CSF were of the pure or mixed eosinophilic variety, coadministration of bryostatin 1 resulted in a dramatic inhibition of eosinophilic colonies and a corresponding increase in pure and mixed neutrophil and macrophage colonies. Although coadministration of recombinant granulocyte colony-stimulating factor (rG-CSF) or recombinant colony-stimulating factor-1 (rCSF-1) mimicked the capacity of bryostatin 1 to increase the total number of pIXY 321-induced day-14 CFU-GM, these growth factors, unlike bryostatin 1, were not capable of inhibiting eosinophilic colony formation. Furthermore, whereas addition of neutralizing antibodies to G-CSF or CSF-1 blocked the capacity of these growth factors to potentiate colony formation in the presence of pIXY 321, it did not abrogate the effect of bryostatin 1 on progenitor cell growth or lineage commitment. Finally, in contrast to its effects on committed myeloid progenitors, bryostatin 1 did not increase the growth of erythroid (burst-forming units-erythroid [BFU-E]) and multipotent (multipotent colony-forming units [CFU-GEMM]) progenitors stimulated by pIXY 321, but instead inhibited colony formation at higher concentrations (e.g., 10 to 100 nM).(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies↗
PubMed1994

The macrocyclic lactone protein kinase C activator, bryostatin 1, either alone, or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor, protects Balb/c and C3H/HeN mice from the lethal in vivo effects of ionizing radiation.

We have examined the in vivo radioprotective effects of the macrocyclic lactone protein kinase C (PK-C) activator, bryostatin 1, administered either alone or in conjunction with recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF), in Balb/c and C3H/HeN mice subjected to lethal total body irradiation (TBI). When administered alone on a divided dose schedule (24 hours and 30 minutes before TBI), rmGM-CSF (20 micrograms/kg) was ineffective in increasing survival in either strain. However, in Balb/c mice, bryostatin 1 alone (1 microgram) permitted the long-term survival (60 days) of 70% of the animals following TBI, and 80% when administered in conjunction with rmGM-CSF. Bryostatin 1 administered alone according to this schedule exerted minimal radioprotective effects in C3H/HeN mice, but, when combined with a subeffective dose of rmGM-CSF, allowed 50% of the animals to survive. Treatment of Balb/c mice with bryostatin 1 administered as a single dose 4 hours before TBI resulted in a 20% survival rate, and 45% when administered with rmGM-CSF; corresponding values for the C3H/HeN strain were 60% and 40%, respectively. Lastly, the survival rates of Balb/c mice treated with bryostatin 1 administered as a single dose 4 hours following TBI was 20%, and 25% with rmGM-CSF; corresponding values were 50% and 25% for C3H/HeN mice. These findings indicate that the PK-C activator bryostatin 1 exhibits intrinsic in vivo radioprotective effects in lethally irradiated Balb/c and C3H/HeN mice, and may, under some circumstances, augment the radioprotective capacity of rmGM-CSF. They also underscore the critical role that strain differences and scheduling considerations play in determining the in vivo radioprotective capacity of bryostatin 1, as well as its interactions with rmGM-CSF.

Animals↗
PubMed1994

Immunogenicity in rabbits and mice of an antibody-chelate conjugate: comparison of (S) and (R) macrocyclic enantiomers and an acyclic chelating agent.

The macrocyclic bifunctional chelating agent 2-(p-bromoacetamidobenzyl)-1,4,7,10-tetraazacyclododecanetetraa cetic acid (BAD), forms inert metal complexes ideal for radioimmunotherapy. Kosmas et al. (Cancer Res., 52: 904-911, 1992) found 2-imminothiolane linker-(S)-BAD monoclonal antibody HMFG1 highly immunogenic in patients. We studied the immunogenicity of (S) and (R) enantiomers of 2-imminothiolane linker-BAD rabbit IgG, monoclonal antibody Lym-1, and Lym-1 2-imminothiolane linker-(S)-bromoacetamidobenzyl-EDTA in 15 rabbits. Five groups of three each were given 0.1, 1.0, or 10 mg of 111In conjugate i.v., blood samples were taken daily for 14 days and biweekly for 70 days, and the plasma T1/2 was calculated. A drop in plasma 111In at 6-8 days coincided with the appearance of antibody on enzyme-linked immunosorbent assay. Specific anti-(S)-BAD, anti-(R)-BAD, anti-(S)-bromoacetamidobenzyl-EDTA, and anti-mouse IgG were measured. Rabbit IgG conjugates did not elicit an immune response. Mouse IgG conjugates were immunogenic on the first exposure, with both anti-1,4,7,10-tetraazacylododecane N,N',N'',N'''-tetraacetic acid and anti-mouse responses. Anti-1,4,7,10-tetraazacylododecane N,N',N'',N'''-tetraacetic acid was specific for the (S) or (R) enantiomer, but cross-reaction appeared with reboosting. A second injection of the opposite enantiomer gave a response to that enantiomer. Lym-1 bromoacetamidobenzyl-EDTA produced anti-bromoacetamidobenzyl-EDTA and anti-mouse response.

Animals↗
PubMed1998

Effects of macrocyclic lactones on ingestion in susceptible and resistant Haemonchus contortus larvae.

The effects of ivermectin and ivermectin aglycone on pharyngeal uptake of a carbohydrate substrate (3H-inulin) were measured in larvae of a macrocyclic lactone (ML)-susceptible isolate and 2 ML-resistant isolates of Haemonchus contortus. The resistant isolates showed a tolerance (in terms of the concentration of compound required to reduce feeding to 50%) toward ivermectin of approximately 4.5- and 9-fold and toward ivermectin aglycone of approximately 14-fold, compared to the susceptible isolate. This indicates that susceptible and resistant isolates can be readily distinguished on the basis of the sensitivity of pharyngeal uptake to MLs. The use of various metabolic inhibitors in this assay system did not reveal the nature of the resistance mechanism. Pretreatment of resistant larvae with inhibitors of multidrug resistance mechanisms (P-glycoprotein and multidrug resistance protein) and detoxification enzymes (monooxygenases, esterases, and glutathione transferases) did not reduce their level of tolerance to the ivermectin aglycone.

Animals↗
PubMed1998

Macrocyclic Cu(II)tetraanhydroaminobenzaldehyde complex--antiproliferative activity in vitro and in vivo.

The macrocyclic Cu(II)-tetraanhydroaminobenzaldehyde complex Cu(TAAB)C12 induces various cytotoxic effects in the dependence on a cell line, concentration and time of exposition. The highest complex concentration of 914 nmol/l induces degeneration of certain part of the HeLa cells population after 24 hours of cultivation. The concentration of 183 nmol/l causes a delayed cytotoxic effect on HeLa and HepG2 cells. After 24 hours of culturing 15.4-28.4% of cell population proliferated but after 48 and 72 hours 2.0-42.3% of the cell population degenerated. The cytotoxic effect on V79 cells is directly dependent on the actual concentration and time of the complex influence. The cytotoxic concentrations of Cu(TAAB)Cl2 induce an integrity damage of cytoplasmatic membrane and two phase unbalanced growth. Cu(TAAB)Cl2 possesses an antileukemic activity which at the dose of 10 mg/kg of body weight is not accompanied by side toxic effects on mice.

Animals↗
PubMed2001

[2.2]paracyclophane/dehydrobenzoannulene hybrids: transannular delocalization in open-circuited conjugated macrocycles.

Enhanced global delocalization throughout the "stepped" π-electron systems of the [2.2]paracyclophane/dehydrobenzoannulene (PC/DBA) hybrids 1 and 2 is strongly suggested by a comparison of their electronic absorption spectra with those of model compounds with complete and interrupted classical aromatic delocalization. A distinct bathochromic shift (for 1) and greater absorption intensity at higher wavelengths (for 1 and 2) is observed versus the corresponding model hydrocarbons.

alkynes↗
PubMed2001

Conjugated complexes composed of quinonediimine and palladium: controlled formation of a conjugated trimetallic macrocycle.

A triangle with a calixarene-like cone configuration: the trimetallamacrocycle [{Pd(en)(L)}3 ](6+) (1; L=N,N'-bis(4-dimethylaminophenyl)-1,4-benzoquinonediimine, en=ethylenediamine; see picture for a space-filling view). The coordination array of the redox-active π-conjugated bridging quinonediimine spacer of L and the palladium unit determines whether conjugated 1 or a conjugated polymeric complex is formed.

bridging ligands↗