RESUMEN
A virtual library of 54 inositol analog mimics of In(1,4,5)P3 has been docked, scored, and ranked within the binding site of human inositol 1,4,5-trisphosphate 3-kinase A (IP3-3KA). Chemical synthesis of the best scoring structure that also met distance criteria for 3'-OH to -P in Phosphate has been attempted along with the synthesis of (1S,2R,3S,4S)-3-fluoro-2,4-dihydroxycyclohexanecarboxylic acid as an inositol analog, useful for non-invasive visualization and quantitation of IP3-3KA enzymatic activity.
RESUMEN
A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.
Asunto(s)
Antineoplásicos/química , Nitrilos/química , Piridinas/química , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cianoacrilatos , Dimerización , Humanos , Modelos Moleculares , Mieloma Múltiple/tratamiento farmacológico , Nitrilos/farmacología , Nitrilos/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/metabolismoRESUMEN
A gram scale synthesis of the glucuronide metabolites of curcumin were completed in four steps. The newly synthesized curcumin glucuronide compounds 2 and 3 along with curcumin 1 were tested and their anti-proliferative effects against KBM-5, Jurkat cell, U266, and A549 cell lines were reported. Biological data revealed that as much as 1 µM curcumin 1 exhibited anticancer activity and almost 100% cell kill was noted at 10 µM on two out of four cell lines; while curcumin mono-glucuronide 2 as well as di-glucuronide 3 displayed no suppression of cell proliferation.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Curcumina/farmacología , Línea Celular Tumoral , Curcumina/síntesis química , Humanos , Células Jurkat , Relación Estructura-ActividadRESUMEN
An improved method for the synthesis of 17ß-hydroxy-16α-iodo-wortmannin along with the first synthesis of 17ß-hydroxy-16α-iodoPX866 and [(131)I] radiolabeled 17ß-hydroxy-16α-[(131)I]iodo-wortmannin, as potential PET tracers for PI3K was also described. The differences between wortmannin and its iodo analogue were compared by covalently docking each structure to L833 in PI3K.
Asunto(s)
Androstadienos/química , Androstadienos/síntesis química , Gonanos/síntesis química , Radiofármacos/síntesis química , Sitios de Unión , Gonanos/química , Radioisótopos de Yodo/química , Marcaje Isotópico , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasa/química , Fosfatidilinositol 3-Quinasa/metabolismo , Tomografía de Emisión de Positrones , Estructura Terciaria de Proteína , Radiofármacos/química , WortmaninaRESUMEN
The C1-C6 region of the potent cytotoxic agent psymberin has been synthesized. The key transformations of the synthesis are an auxiliary-controlled addition of a Sn(II)-glycolate enolate to an aldehyde to yield the anti aldol product and transforming the primary alcohol into a terminal olefin utilizing organoselenium chemistry.
RESUMEN
A procedure for the asymmetric synthesis of a novel ß-hydroxy-α-amino acid deriverative to be used in the preparation of the natural product MPC1001 and analogs has been developed. The amino acid was efficiently prepared in six steps via a Mukaiyama aldol reaction via a diphenyloxazinone and 3-bromo-4-methoxybenzaldehyde.
RESUMEN
A novel [1,3]-dipolar azomethine ylide cycloaddition has been developed in an approach to the synthesis of the MPC1001 family of natural products.