ABSTRACT
The "Instrumental Revolution" in chemistry refers to a transitional period in the mid-20th century during which sophisticated instrumentation based on physical principles was introduced to solve chemical problems. Historical and philosophical reflection on whether the revolution was a scientific one has been dominated by general models of scientific revolution, in particular, those proposed by Thomas Kuhn, I. B. Cohen and Ian Hacking. In this article I propose that the Industrial Revolution is a useful model for understanding the transformation wrought by the increasingly important role of machines in chemical research. Drawing on Marx's analysis of that event, I argue that that the Instrumental Revolution bears a striking resemblance to the industrial one. I offer grounds for thinking that the resemblance is not fortuitous, but rather reflects a general pattern of development involving the mechanization of the labor process. It is suggested that the cognitive consequences of radical changes in the means of production, as exemplified in the Instrumental Revolution, warrant the consideration of whether the latter is an instance of a kind of revolution in science rather than a singular episode.
ABSTRACT
The use of cyclic α,ß-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.
Subject(s)
Alkadienes/chemistry , Alkaloids/chemical synthesis , Aza Compounds/chemical synthesis , Imines/chemistry , Lactones/chemical synthesis , Spiro Compounds/chemical synthesis , Alkaloids/chemistry , Aza Compounds/chemistry , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Lactones/chemistry , Molecular Structure , Spiro Compounds/chemistry , StereoisomerismABSTRACT
We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
Subject(s)
Antineoplastic Agents/pharmacology , Endothelial Cells/drug effects , Naphthalenes/pharmacology , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Corneal Neovascularization/blood , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Female , Humans , Inhibitory Concentration 50 , Injections, Intravenous , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/drug effects , Models, Molecular , Molecular Structure , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.
