摘要:
This invention provides a compound having the structure: wherein R1 is H, halogen, —NR5R6, —NR5—C(═O)—R6, —NH—C(═O)—OR7, —OR7, —NO2, —CN, —SR7, —SO2R7, —CO2R7, CF3, —SOR7, —POR7, —C(═S)R7, —C(═O)—NR5R6, —CH2—C(═O)—NR5R6, —C(═NR5)R6, —P(═O)(OR5)(OR6), —P(OR5)(OR6), —C(═S)R7, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R5, R6, and R7 and are each, independently, H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; R2 and R3 are each, independently, H, halogen, —NH2, —CX3, —C(═O)OR8, C(═O)R8, —C(═O)NR9R10, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl; wherein X is Cl, Br, or F; R8, R9 and R10 are each, independently, H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Q is —Ar1—Z— or —Z—Ar1—Z—, wherein Ar1 is aryl or heteroaryl; and each occurrence of Z is independently present or absent, and when present is —O—, —S—, —CH2—, —C(O)——NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH2NH—, —NHC(═O)CH2C(═O)—, —N(OH)—, —CH2CH2— or —NHC(═O)CH═CH—; and R4 is alkyl, —OR11 or —NH—OR11, wherein R11 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl, and when Q is —Ar1—Z—, Z is absent, Ar1 is phenyl, R2 and R3 are H, n=1, and R4 is —NHOH, then R1 is other than carbazole, tetrahydro-&bgr;-carboline, tetrahydro-γ-carboline, —C(═O)—NR5R6 and —NR5—C(═O)—R6, wherein one of R5 or R6 is quinoline and the other of R5 or R6 is H; or a pharmaceutically acceptable salt thereof.
摘要:
The invention provides compounds, several of which belong to a class having two or more nonpolar components connected by a polar group and having polar groups on the termini of the compound. The invention also concents a method of selectively inducing termini differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable condition with an amount of the compound effective to selectively induce terminal differentiation. Moreover, the invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an amount of the compound effective to selectively induce terminal differentiation of such neoplastic cells, thereby inhibiting their proliferation and suppressing oncogenicity. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound in an amount effective less than an amount which would cause toxicity in the patient.
摘要:
The present invention provides three-dimensional structural information from the hyperthermophilic bacterium Aquifex aeolicus which is a histone deacetylase-like protein (HDLP). HDLP shares 35.2% amino acid sequence identity with human histone deacetylase (HDAC1). The present invention further provides three-dimensional structural information of HDLP bound by inhibitor molecules. The three-dimensional structural information of the present invention is useful to design, isolate and screen deacetylase inhibitor compounds capable of inhibiting HDLP, HDAC family members and HDLP-related molecules. The invention also relates to nucleic acids encoding a mutant HDLP which facilitates the determination of the three-dimensional structure of HDLP in the presence of a zinc atom.