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7 results on '"Leif M. Laakso"'

1. Pyranonaphthoquinone Lactones: A New Class of AKT Selective Kinase Inhibitors Alkylate a Regulatory Loop Cysteine

Author

Cilien Hanna, Clark Eid, Erick Honores, Weiguo Zhang, Leif M. Laakso, Ayako Yamashita, Bernard Dean Johnson, Leonard A. McDonald, Zhong Li, Weidong Ding, Dennis Powell, Jeremy I. Levin, Girija Krishnamurthy, Keiko Tabei, Jaechul Shim, Edward J. Salaski, Shabana Insaf, Lourdes Toral-Barza, Ker Yu, and Tarek S. Mansour

Subjects
Alkylation, Stereochemistry, Antineoplastic Agents, Lactones, Structure-Activity Relationship, Cell Line, Tumor, Drug Discovery, medicine, Humans, Structure–activity relationship, Cysteine, Protein kinase B, Cell Proliferation, Pyrans, chemistry.chemical_classification, biology, Kinase, Stereoisomerism, Oncogene Protein v-akt, Enzyme, chemistry, Mechanism of action, Biochemistry, Enzyme inhibitor, biology.protein, Molecular Medicine, medicine.symptom, Signal transduction, Biomarkers, Naphthoquinones
Abstract

The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.

Published
2009

2. Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Author

Wei Li, Qin Wang, Jason Shaoyun Xiang, Jeremy I. Levin, Leif M. Laakso, Xuemei Du, Thomas S. Rush, Jennifer R. Thomason, Manus Ipek, Tam Steve Yik-Kai, Yonghan Hu, Jerauld S. Skotnicki, Jean Schmid, Martin J. DiGrandi, and Jianchang Li

Subjects
Models, Molecular, Clinical Biochemistry, Drug Evaluation, Preclinical, Administration, Oral, Pharmaceutical Science, Osteoarthritis, Matrix Metalloproteinase Inhibitors, Matrix metalloproteinase, Pharmacology, Biochemistry, Substrate Specificity, Inhibitory Concentration 50, Pharmacokinetics, Oral administration, Matrix Metalloproteinase 13, Drug Discovery, medicine, Animals, Collagenases, Enzyme Inhibitors, Molecular Biology, Benzofurans, chemistry.chemical_classification, Molecular Structure, biology, Organic Chemistry, medicine.disease, Bovine Cartilage, Rats, Bioavailability, Enzyme, chemistry, Enzyme inhibitor, biology.protein, Molecular Medicine
Abstract

Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated50% inhibition of bovine cartilage degradation at 10 ng/mL.

Published
2005

3. Formal total synthesis of FK506. Concise construction of the C(10)-C(34) segment via an effective coupling tactic

Author

Leif M. Laakso, Karl J. Hale, Kwunmin Chen, Darius J. Robinson, and Amos B. Smith

Subjects
chemistry.chemical_classification, Olefin fiber, Chemistry, Stereochemistry, Organic Chemistry, Iodide, Acetal, Total synthesis, Ether, Nanotechnology, Biochemistry, Aldehyde, chemistry.chemical_compound, Drug Discovery, Stereoselectivity, Dithiane
Abstract

A formal total synthesis of the potent immunosuppressant FK506 (1) has been achieved via a concise construction of the Merck advanced intermediate (−)-2. Key features of the successful strategy include stereocontrolled σ-bond installation of the trisubstituted olefin moieties and an efficient coupling of the C(24)-C(34) dithiane (−)-10 with the C(10)-C(23) α-silyloxy primary iodide (−)-9.

Published
1994

6. Oxazole Diels–Alder Reactions

Author

Leif M. Laakso and Jeremy I. Levin

Subjects
chemistry.chemical_compound, Isoindoles, chemistry, Singlet oxygen, Diels alder, Organic chemistry, Eupolauramine, Gnididione, Aryne, Stemoamide, Oxazole
Published
2003

7. FK-506 synthetic studies. 3. An efficient asymmetric synthesis of the C(24)–C(34) fragment of FK-506, FR-900520, and FR-900523

Author

Karl J. Hale, Leif M. Laakso, Antoni Riera, Amos B. Smith, and Kwunmin Chen

Subjects
Fragment (logic), Stereochemistry, Chemistry, Organic Chemistry, Drug Discovery, Enantioselective synthesis, Biochemistry, Combinatorial chemistry
Abstract

An efficient asymmetric synthesis of the C(24)–C(34) fragment of the FK-506 family of immunosuppressants has been achieved.

Published
1989

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