Harvard College

Other

President and Fellows of Havard College

Andrew G Myers

Jason D Brubaker

Ziyang Zhang

Ian Bass Seiple

Christian D Lerner

Mark G Charest

Dionicio R Siegel

Daniel Jonathan Smaltz

Matthew D Shair

Alec Nathanson Flyer

Hong Myung Lee

Chong Si

Cristina Montserrat Nieto-Oberhuber

Matthew James Mitcheltree

Jakub Svenda

Jason D Brubacker

Evan Hecker

Alleyn T Plowright

David A Kummer

Derun Li

Amelie Dion

Peter M Wright

Nicholas E Hill

Robert T Yu

Katherine J Silvestre

Thomas Magauer

Andreas Schumacher

Roger B Clark

Binyuan Sun

Seth Herzon

Cuixiang Sun

Daniel W Kung

Xiben Li

Jeremy Earle Wulff

Takehiro Fukuzaki

Romain Siegrist

Matthew Allen Zajac

Stona R Jackson

Jacob R LaPorte

Chengguo Xing

Brian Lanman

Wenying Wang

Sushmita D Lahiri

Udara Anulal Premachandra Ilandari Dewage

Jonathan F Lawrence

Senkara Rao Allu

Wesley Francis Austin

Yoshitaka Ichikawa

Qiu Wang

Peter Maughan Wright

Thomas Maguer

Provided are lincosamide compounds for the treatment of infectious diseases. The lincosamides described herein are modified at the amino acid (southern) region. The lincosamides may have further modification at the C-1 and C-7 positions of the aminooctose (northern) region, thus distinguishing them from lincomycin and clindamycin. Also provided are methods for preparing the lincosamide compounds, pharmaceutical compositions comprising the lincosamide compounds, and methods of treating infectious diseases using the disclosed lincosamide compounds.

Lincosamide antibiotics and uses thereof

Provided are macrolide compounds for the treatment of infectious diseases. The macrolides disclosed herein include 14-membered ketolides and 14-15-membered azaketolides, and may comprise modified sugars which are desosamine analogues. The disclosed macrolides may have a bicyclic structure. Also provided are pharmaceutical compositions and methods of treating infectious diseases, and in particular, disease which results from Gram negative bacteria using the disclosed macrolides. This disclosure additionally provides methods of preparing the macrolides by a strategy that enables late-stage modification of the 6'-position of the sugar moiety, thereby allowing facile access to previously difficult-to-make macrolide compounds.

Macrolides with modified desosamine sugars and uses thereof

Provided herein are methods of preparing macrolides by the coupling of an eastern and western half, followed by macrocyclization, to provide macrolides, including both known and novel macrolides. Intermediates in the synthesis of macrolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using the inventive macrolides are also provided. A general diastereoselective aldol methodology used in the synthesis of the western half is further provided.

Macrolides and methods of their preparation and use

Provided are lincosamide compounds for the treatment of infectious diseases. The lincosamides described herein are modified at the C-7 position of the aminooctose (northern) region, thus distinguishing them from lincomycin and clindamycin. Also provided are methods for preparing the lincosamide compounds, pharmaceutical compositions comprising the lincosamide compounds, and methods of treating infectious diseases using the disclosed lincosamide compounds.

Provided herein are macrolide compounds of Formula (I) and (I-N) for the treatment of infectious diseases and inflammatory conditions. The 14-membered ketolides and 14-, 15-, and 16-membered azaketolides described herein comprise modified sugars which are desosamine or mycaminose analogs. Pharmaceutical compositions and methods of treating infection diseases and inflammatory conditions using the inventive macrolides are also provided. This disclosure additionally provides methods of preparing the macrolides by the coupling of an eastern and western half. 

Provided herein are methods of preparing new 14-membered ketolides via coupling of an eastern and western half moiety, followed by macrocyclization, and optional functionalization. Intermediates in the synthesis of these ketolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using these ketolides are also provided.

14-membered ketolides and methods of their preparation and use

The tetracycline class of antibiotics has played a major role in the treatment of infectious diseases for the past 50 years. However, the increased use of the tetracyclines in human and veterinary medicine has led to resistance among many organisms previously susceptible to tetracycline antibiotics. The modular synthesis of tetracyclines and tetracycline analogs described provides an efficient and enantioselective route to a variety of tetracycline analogs and polycyclines previously inaccessible via earlier tetracycline syntheses and semi-synthetic methods. These analogs may be used as anti-microbial agents or anti-proliferative agents in the treatment of diseases of humans or other animals.

Synthesis of tetracyclines and analogues thereof

The present invention provides desosamine and mycaminose analogs and nitro sugars and methods for their preparation. The invention also provides methods of cyclizing a compound of Formula (A') with glyoxal to give a nitro sugar of Formula (B). Methods for the preparation of compound of Formula (D&#x2032;) are provided comprising cyclization of a nitro alcohol to give a nitro sugar and reduction and alkylation of the nitro sugar to give a desosamine, mycaminose, or an analog thereof. 

Synthesis of desosamines

Provided herein are trioxacarcin-antibody drug conjugates of Formula (A): and pharmaceutically acceptable salts thereof, comprising at least one instance of the group -L-(A-L)-B attached thereto, wherein a is an integer between 1 and 10, inclusive, Lis absent or is a linking group, A is a moiety formed from the reaction of two complimentary groups (X and Y), Lis absent or is another linking group, and B is an antibody or antibody fragment. Also provided are methods of preparing these antibody-drug conjugates, pharmaceutically acceptable compositions thereof, and methods of their use and treatment. Further provided are precursors to the trioxacarcin-antibody drug conjugates, novel trioxacarcins without an antibody conjugated thereto, pharmaceutical compositions thereof, and methods of their use and treatment.

Trioxacarcins, trioxacarcin#antibody conjugates, and uses thereof

Provided herein are methods of preparing new 14-membered ketolides via coupling of an eastern and western half moiety, followed by macro-cyclization, and optional functionalization. Intermediates in the synthesis of these ketolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using these ketolides are also provided.

Growing community of inventors

Boston, MA, United States of America

Andrew G Myers