Leptomycin compounds
Inventors
Dong, Steven • Santi, Daniel V. • Myles, David C. • Hearn, Brian
Assignees
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Publication Number
US-7446196-B2
Publication Date
2008-11-04
Expiration Date
Abstract
Leptomycin-type compounds according to Formula I wherein R0, R1, R2, R10, R11, R12, R13, R14, and m are as defined herein, exhibit anti-tumor activity.
Core Innovation
The invention relates to leptomycin B-derived compounds having a structure according to formula Ia, with variable m selected from 0, 1, 2, 3, 4, or 5 and defined substituents R1-R6. The compounds include alternative ring-forming conditions in which R5 and R6, together with the nitrogen to which they are commonly bonded, form a 4, 5, 6, or 7 membered nitrogen-containing heterocyclic ring structure.
The disclosed compounds act through inhibition of CRM1 (nuclear export), including formation of a covalent adduct at CRM1/Cys529, which results in nuclear trapping of proteins including p53 and Bcr-Abl and induces apoptosis. The disclosure also identifies fluorescent labeling, where R6 optionally includes a fluorescent moiety so that a fluorescent probe bearing leptomycin B compounds retains cytotoxic activity and can serve as a biomarker.
The patent addresses treatment of a wide range of cancers and hyperproliferative disorders and describes pharmaceutical use in hyperproliferative diseases, including specific human cancers such as breast, lung, ovarian, prostate, leukemia, HPV-associated cervical cancer, and bladder cancer. The specification further discusses synergistic combinations, including combinations with imatinib (Gleevec), as well as biological testing and comparative in vitro cytotoxicity results relative to leptomycin B.
Claims Coverage
The independent claim is directed to a formula Ia compound with detailed substituent constraints, and the dependent claims further narrow the moiety selection, add a pharmaceutical composition with an excipient, and specify a particular illustrated molecular structure. The coverage centers on one main structural formula with multiple inventive feature groupings, including the m-dependent restriction on R3 and the optional fluorescent moiety or ring-forming condition for R5 and R6.
Formula Ia compound with constrained substituents
A compound having a structure according to formula Ia, wherein m is 0-5; R1 is H, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 alkynyl; R2 is H, aryl, cycloalkyl, or a heterocyclic moiety; R3 is H, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 alkynyl provided that R3 is not H where m is 0; R4 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl, cycloalkyl, or a heterocyclic moiety; R5 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, aryl, cycloalkyl, a heterocyclic moiety, or C(=O)O(C1-C5 alkyl); and R6 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, cycloalkyl or a fluorescent moiety, with an alternative where R5 and R6 and the nitrogen to which they are commonly bonded form a 4, 5, 6, or 7 membered nitrogen-containing heterocyclic ring structure.
Selected moiety set for formula Ia
A compound according to claim 1, wherein the moiety in formula Ia is selected from the group consisting of the specified structures in the provided formula images.
Pharmaceutical composition including excipient
A pharmaceutical composition comprising a compound according to claim 1 and an excipient.
Specific illustrated molecular structure instance
A compound of claim 1 having the formula as specified by the illustrated molecular structure.
Claim coverage centers on a formula Ia compound with detailed substituent and ring-forming constraints, including the m-dependent restriction on R3, and is further narrowed by selecting the formula Ia moiety from a specified group of structures and by pharmaceutical compositions including an excipient and specific illustrated formula instances.
Stated Advantages
Inhibiting CRM1-mediated nuclear export.
Inhibiting target-cell proliferation.
Fluorescent probe bearing leptomycin B compounds retains cytotoxic activity.
Fluorescent probe can serve as a biomarker.
Documented Applications
Pharmaceutical treatment of hyperproliferative diseases, including specific human cancers: breast, lung, ovarian, prostate, leukemia, HPV-associated cervical cancer, and bladder cancer.
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