ABSTRACT
To apply our collection of enantiopure 7-ring vinyl sulfones to probe the anticancer SAR of a series of computer-designed (+)-discodermolide analogs, the ozonolytic reactivity of transposed cyclic vinyl phosphonates was explored. Successful preparation of the desired aldehyde-esters and lactones from vinyl phosphonates via an oxidative cleavage-phosphite/methanol exchange sequence is described.
Subject(s)
Alkanes/chemical synthesis , Carbamates/chemical synthesis , Lactones/chemical synthesis , Organophosphonates/chemistry , Ozone/chemistry , Pyrones/chemical synthesis , Sulfones/chemistry , Vinyl Compounds/chemistry , Alkanes/chemistry , Carbamates/chemistry , Combinatorial Chemistry Techniques , Lactones/chemistry , Models, Molecular , Molecular Structure , Oxidation-Reduction , Pyrones/chemistry , Structure-Activity RelationshipABSTRACT
H5IO6 in the presence of catalytic chromoyl diacetate is a powerful method for oxidation of C-H bonds. Tertiary and oxygen activated C-H bonds are oxidized to tertiary alcohols or ketones at temperatures as low as -40 degrees C. The putative reagent is neutral dioxoperoxy chromium[VI] which undergoes C-H oxidation with retention of stereochemistry. This reagent appears to be the first reagent capable of oxidation of a C-H bond in the presence of an olefin without concomitant epoxidation.
Subject(s)
Chromium/chemistry , Spiro Compounds/chemistry , Catalysis , Cold Temperature , Oxidation-Reduction , Spiro Compounds/chemical synthesisABSTRACT
A series of Taxol derivatives tethered at C2' and C-7 to glutamate and folate have been synthesized for evaluation as prodrugs which release Taxol via hydrolytic lability of their alpha-alkoxy and alpha-amino esters. The half-time for hydrolysis of these materials was determined in pH 7 and pH 5 buffer. The in vitro cytotoxicity has been assessed in cell culture against A-549 lung cancer, MCF-7 breast cancer, and HT-29 colon cancer. Selected agents were further screened for folate binding and competitive binding with free folic acid. One agent (54), further evaluated in animal studies was found to increase the lifespan in mice, but was less effective than Taxol itself.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Folic Acid/chemistry , Paclitaxel/chemistry , Antineoplastic Agents/chemistry , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , Hydrolysis , Magnetic Resonance Spectroscopy , Mass Spectrometry/methods , Tumor Cells, CulturedABSTRACT
Oxidative functionalization (or removal) of a steroidal C18 methyl group is possible using a previously unknown dyotropic rearrangement of a seven-membered fused C-ring lactone to a 6-ring spiro lactone. Spiroketal equilibration led to the 23-deoxy South analogue of cephalostatin 1 (1) in only 12 steps (23% overall yield) from hecogenin acetate 4, and to strained diene South 1 analogue 30 in 11 steps (28% overall). Total synthesis of 23'-deoxy cephalostatin 1 (3) was accomplished in 16 operations from 4 (9% overall; average 86% yield per operation), and that of 16',17'-dehydro-23'-deoxy cephalostatin 1 (36) in 15 operations from 4 (8% overall; av 84%/op).
Subject(s)
Phenazines/chemical synthesis , Spiro Compounds/chemical synthesis , Steroids , Oxidation-Reduction , Phenazines/chemistry , Spiro Compounds/chemistry , Spironolactone/analogs & derivatives , Spironolactone/chemical synthesis , Spironolactone/chemistry , StereoisomerismABSTRACT
[reaction: see text]anti-Oximes of 2-pyridylacetic acid esters are rapidly transformed to pyridine-2-carbonitrile under a variety of conditions while syn-oximes bearing tert-butyl esters can be conveniently deprotected to the corresponding carboxylic acid with subsequent fragmentation to the nitrile.
ABSTRACT
Enantiopure epoxy cycloheptenyl sulfones syn-7b and anti-7b are prepared in five high-yielding and stereospecific operations from 1, 3-cycloheptadiene. These substrates serve as effective precursors for cis- and trans-substituted tetrahydrofurans (12, 10) which are segments of the antineoplastic agent IKD-8344.
Subject(s)
Antineoplastic Agents/chemical synthesis , Furans/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cycloheptanes/metabolism , Furans/chemistry , Furans/metabolism , Molecular Structure , StereoisomerismABSTRACT
[structure: see text] 20- and 25'-epimers of cephalostatin 7, prepared by directed unsymmetrical pyrazine synthesis, address outer-ring topographical and stability questions and intimate an oxacarbenium ion rationale for the role in bioactivity of the spiroketal (E/F, E'/F') rings of this class of antitumor agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Phenazines/chemical synthesis , Spiro Compounds/chemical synthesis , Steroids , Animals , Antineoplastic Agents/toxicity , Humans , Mice , Models, Molecular , Molecular Conformation , Molecular Structure , Neoplasms/drug therapy , Phenazines/toxicityABSTRACT
Analogues 12'beta-hydroxycephalostatin 1 (9), 7'-deoxyritterazine G (10), and 14-epi-7'-deoxyritterazine B (11) were prepared via our protocol for unsymmetrical pyrazine synthesis. Cytotoxicity against human tumors was also determined for the first time for ritterazines, with femtomolar potency and a high correlation to cephalostatins observed. The SAR of these and related compounds provide insight into the importance of topography and certain chemical functionality in the B-D and B'-D' rings of cephalostatin type antineoplastics.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Humans , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Antineoplastic bis-steroidal (cephalostatin-type) analogues of the saponin OSW-1 were produced from a dihydroaglycone of OSW-1. The key aglycone 6H was obtained from 5alpha-androstan-3beta-ol-17-one in 8 steps (38% yield). The SAR of the aglycones, intermediates, and hybrid analogues provide insights regarding the proposed common role of C22-oxocarbenium ions in the bioactivity of both OSW-1 and cephalostatins.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Cholestenones , Saponins/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Saponins/pharmacology , Structure-Activity RelationshipABSTRACT
[formula: see text] Lewis and/or Bronsted acid additives permit ring opening and halogenation of spiroketals at substantially reduced temperatures to produce omega-iodo enol ethers in improved yield and purity, which can undergo further reaction in the presence of distal electrophilic centers to give new steroid skeletons.
Subject(s)
Spiro Compounds/chemical synthesis , Steroids/chemical synthesis , Acids , Catalysis , Halogens , Steroids/chemistryABSTRACT
[formula: see text] Anhydride 3 is a useful reagent for the synthesis of triply linked drug conjugates. Examples using paclitaxel are provided. Conversion of the azido moiety to a primary amine in the presence of substrates bearing labile ester functionality requires the use of tin/mercaptan reducing system which includes methanol exchange equilibration to effect nitrogen-tin bond scission.
Subject(s)
Amines/chemistry , Anhydrides/chemical synthesis , Azides/chemistry , Folic Acid/chemistry , Oxazines/chemical synthesis , Polyethylene Glycols/chemistry , Esters/chemistry , Imino Acids/chemistry , Indicators and Reagents , Oxidation-Reduction , Paclitaxel/chemistryABSTRACT
[formula: see text] Enantiopure epoxy vinyl sulfones serve as highly effective substrates for a variety of stereo- and regiospecific oxidation and nucleophilic functionalization reactions. These materials can be easily transformed to cyclic and acyclic six-carbon segments. Nucleophilic epoxidation of 3a,b followed by palladium[0] catalysis enables access to differentially protected arene diols 21 and 22.
Subject(s)
Epoxy Compounds/chemistry , Sulfones/chemistry , Molecular Conformation , StereoisomerismABSTRACT
Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its gamma-carboxyl group to deferoxamine (DF), and the 67Ga-labeled complex ([67Ga]DF-folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA-folate (gamma) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of [111In]DTPA-folate (gamma) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered [111In]DTPA-folate (gamma) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with [67Ga]DF-folate (gamma) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by gamma scintigraphy 1 h following intravenous administration of [111In]DTPA-folate (gamma).
Subject(s)
Folic Acid/analogs & derivatives , Pentetic Acid/analogs & derivatives , Radiopharmaceuticals/chemical synthesis , Animals , Biotransformation , Cells, Cultured , Chelating Agents/chemistry , Chelating Agents/pharmacokinetics , Drug Design , Folic Acid/chemical synthesis , Folic Acid/pharmacology , Humans , Indium Radioisotopes , KB Cells , Male , Mice , Mice, Nude , Neoplasms, Experimental/diagnostic imaging , Pentetic Acid/chemical synthesis , Pentetic Acid/pharmacology , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/metabolism , Tissue Distribution , Whole-Body CountingABSTRACT
Allylic aryl sulfones bearing an o-allyldialkylstannyl moiety (1b), when converted to stannyl radical 1a, suffer homolytic cleavage via intramolecular attack of the stannyl radical on the sulfone. Allyl radicals generated in this manner can be utilized for further intramolecular radical cyclizations; thus the overall transformation can be viewed as an alkylative desulfonylation reaction. Previously unknown sulfonyl stannane polymer 5 is generated as a byproduct. The o-dibutylstannyl radical derived from nonallylic aryl sulfone 15 does not suffer homolysis but instead forms 9-membered macrocycle 19 via an intramolecular reaction with the phenylacetylene group.
ABSTRACT
Aryl sulfones bearing an o-(bromomethyl)dimethylsilyl moiety (1), when heated with AIBN and tributyltin hydride, suffer radical elimination under mild conditions to give olefins and stannyl sulfinate 7 in high yield. The mechanism is shown to proceed via intramolecular beta-sulfonyl hydrogen abstraction by o-silylmethylene radical 2. This step also shows a large deuterium isotope effect of 12:1. In contrast, radical intermediate 24, generated by tris(trimethylsilyl)silane radical addition to o-allylsilane 23, undergoes intramolecular attack on the sulfone, resulting in homolytic sulfone cleavage to afford reduced products and cyclic sulfone byproduct 25.
ABSTRACT
This study examined graduating student nurse role conception changes that occurred during a concentrated clinical preceptorial. A Nursing Role Conceptions Questionnaire was administered to nursing students before (n = 44) and immediately after (n = 41) a 4-week Nursing Practicum; to the students' staff nurse clinical teaching associates (n = 34); and to nursing program faculty (n = 18). Respondent perceptions of ideal nursing behaviors and actual nursing behaviors within three major nursing roles (professional, service, and bureaucratic) were identified and differences between ideal and actual scores (role discrepancy) were calculated. Findings showed that student role orientation in selected areas changed from a faculty role orientation to a staff nurse role orientation over the 4-week period. The Practicum seemed to effectively facilitate role socialization of graduating student nurses into the work setting, easing the necessary transition from education to practice.
Subject(s)
Education, Nursing , Professional Practice , Role , Socialization , Students, Nursing/psychology , Education, Nursing/statistics & numerical data , Faculty, Nursing/statistics & numerical data , Humans , Indiana , Nursing Education Research/statistics & numerical data , Professional Practice/statistics & numerical data , Students, Nursing/statistics & numerical data , Surveys and QuestionnairesABSTRACT
Human platelets have been employed as an assay system to evaluate the pharmacological activity of a group of stable, arene-fused prostacyclin analogs. Prostacyclin (PGI2) is a highly active member of the eicosanoid family and is relatively unstable under physiological conditions. Prostacyclin's best characterized activities are those of inhibition of platelet aggregation and relaxation of vascular smooth muscle. These activities are mediated in large part via elevation of intracellular levels of cyclic AMP subsequent to receptor occupation and activation of adenylate cyclase. We previously described the synthesis of a series of arene-fused prostacyclin analogs with stability in aqueous media at physiological pH. Several of these compounds have prostacyclin-like activities, i.e., competitive binding at the platelet prostacyclin receptor, elevation of intraplatelet cyclic AMP levels and inhibition of human platelet aggregation. One compound in particular (11a) demonstrated these activities with potency similar to PGI2, i.e., Kd at platelet receptor of 3.7 nM and IC50 for inhibition of collagen-induced human platelet aggregation in plasma of 2.9 nM.
Subject(s)
Blood Platelets/drug effects , Epoprostenol/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Vasodilator Agents/pharmacology , Blood Platelets/metabolism , Cyclic AMP/metabolism , Epoprostenol/analogs & derivatives , Epoprostenol/chemical synthesis , Humans , In Vitro Techniques , Receptors, Epoprostenol , Receptors, Prostaglandin/metabolismABSTRACT
The intramolecular migration of a trimethylsilyl moiety alpha to a sulfone group of some modified cyclohexyl ring systems is investigated. The large difference in the relative abundance of this rearrangement ion for similar compounds is related to the stability of the protonated species.
Subject(s)
Sulfones/chemistry , Trimethylsilyl Compounds/chemistry , Mass SpectrometryABSTRACT
Metering liquid reagents into reaction mixtures in a controlled and reproducible manner has often been a problem in synthetic chemistry. Carrying out the real simultaneous addition of two or more liquid reagents (concurrent additions) is even more inconvenient. Difficulties increase when addition volumes become small, when addition times become long, or when the reagents are corrosive or air-sensitive. We have constructed and tested an inexpensive, automated device for the slow, precise delivery of liquid reagents into laboratory-scale reaction mixtures. Controlled by a standard personal computer, this slow adder can accommodate liquid volumes from hundreds of microlitres to litres and addition times from minutes to days. Its glass and Teflon construction makes it useful for nearly all reagents. By using multiple slow adders, true concurrent addition of several liquids can be easily achieved.