- HINDERED DISULFIDE DRUG CONJUGATES
-
The invention relates generally to disulfide drug conjugates wherein a linker comprising a sulfur-bearing carbon atom substituted with at least one hydrocarbyl or substituted hydrocarbyl is conjugated by a disulfide bond to a cysteine sulfur atom of a targeting carrier, and wherein the linker is further conjugated to a drug moiety. The invention further relates to activated linker-drug conjugates suitable for conjugation to a targeting carrier by a disulfide bond. The invention further relates to methods for preparing hindered disulfide drug conjugates.
- -
-
Page/Page column 127; 140; 141
(2017/05/02)
-
- ANTI-BACTERIAL COMPOUNDS
-
A compound of Formula (II): for use in the prevention or treatment of a bacterial infection.
- -
-
Page/Page column 90
(2017/06/28)
-
- Discovery and synthesis of hydronaphthoquinones as novel proteasome inhibitors
-
Screening efforts led to the identification of PI-8182 (1), an inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. Compound 1 contains a hydronaphthoquinone pharmacophore with a thioglycolic acid side chain at position 2 and thiophene sulfonamide at position 4. An efficient synthetic route to the hydronaphthoquinone sulfonamide scaffold was developed, and compound 1 was synthesized in-house to confirm the structure and activity (IC50 = 3.0 ± 1.6 μM [n = 25]). Novel hydronaphthoquinone derivatives of 1 were designed, synthesized, and evaluated as proteasome inhibitors. The structure-activity relationship (SAR) guided synthesis of more than 170 derivatives revealed that the thioglycolic acid side chain is required and the carboxylic acid group of this side chain is critical to the CT-L inhibitory activity of compound 1. Furthermore, replacement of the carboxylic acid with carboxylic acid isosteres such as tetrazole or triazole greatly improves potency. Compounds with a thio-tetrazole or thio-triazole side chain in position 2, where the thiophene was replaced by hydrophobic aryl moieties, were the most active compounds with up to 20-fold greater CT-L inhibition than compound 1 (compounds 15e, 15f, 15h, 15j, IC50 values around 200 nM, and compound 29, IC50 = 150 nM). The synthetic iterations described here not only led to improving potency in vitro but also resulted in the identification of compounds that are more active such as 39 (IC50 = 0.44 to 1.01 μM) than 1 (IC50 = 3.54 to 7.22 μM) at inhibiting the proteasome CT-L activity in intact breast cancer cells. Treatment with 39 also resulted in the accumulation of ubiquitinated cellular proteins and inhibition of tumor cell proliferation of breast cancer cells. The hit 1 and its analogue 39 inhibited proteasome CT-L activity irreversibly.
- Ge, Yiyu,Kazi, Aslamuzzaman,Marsilio, Frank,Luo, Yunting,Jain, Sanjula,Brooks, Wesley,Daniel, Kenyon G.,Guida, Wayne C.,Sebti, Sa?d M.,Lawrence, Harshani R.
-
scheme or table
p. 1978 - 1998
(2012/05/04)
-
- Tricyclic compounds with pharmaceutical activity
-
The invention relates to tricyclic compounds of formula (I) STR1 wherein R1 is hydrogen, amino, (1-4C)alkyl, (1-4C)alkoxy, hydroxy-(1-4C)alkyl or fluoro-(1-4C)alkyl; R2 is hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, hydroxy-(2-4C)alkyl, halogeno-(2-4C)alkyl or cyano-(1-4C)alkyl; Ar is optionally-substituted phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl; and R3 includes a group of the formula --NHCH(CO2 H)--A1 --Y1 wherein A1 is (1-6C)alkylene and Y1 is carboxy, tetrazol-5-yl, N-?(1-4C)alkylsulphonyl!carbamoyl, N(phenylsulphonyl)carbamoyl, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; or pharmaceutically-acceptable salts or esters thereof; to processes for their manufacture; to pharmaceutical compositions containing them; and to their use as anti-cancer agents.
- -
-
-
- Cephalosporin displacement reaction
-
The present invention is directed to a process for the displacement of the acetoxy group of a cephalosporanic acid by a sulfur nucleophile, in an organic solvent and under essentially anhydrous conditions.
- -
-
-
- 7-(3-Substituted ureido) cephalosporins
-
Cephalosporin compounds with 3-substituted ureido or -thioureido group at position 7 and hydrogen or heterocyclicthiomethyl groups at position 3 are prepared. These compounds are antibacterial agents.
- -
-
-
