Download 786_Intro

US 6,743,786
Vanadium Compounds for
Treating Cancer
Chrissy Brown (PO)
Lisa Perlson (AI)
November 15, 2006
PO
Claimed Invention: VCp2(bpy)OTf2
Abbreviations
V – Vanadium(IV)
Cp – Cyclopentadienyl Ring
Bpy – 2,2’-Bipyridine
OTf2 – Triflate (CF3SO3- )
 Used to treat Leukemia, Hodgkin’s Lymphoma, non-Hodgkin’s
Lymphoma, Multiple Myeloma, Testicular Cancer, Brain Tumor, Breast
Cancer and Prostate Cancer
PO
Anticancer Activity of VCp2Cl2
VCp2Cl2 and TiCp2Cl2 are well known anti-cancer agents.
 Comparable activity in mammary, lung, colon and skin cancer
 For testicular, brain and leukemia cancers, only V showed anticancer activity (Unexpected Result)
In Vitro Cytotoxicity of Vanadocene
Compounds Against Human Cancer
 VDC = VCp2Cl2
PO
Monodentate v. Bidentate VCp2 Ligands
 Monodenate Ligands
Single Coordination to Metal
Ex: Cl, CN, SCN
 Bidentate Ligands
Double Coordination to Metal
Ex: Bipyridine
V
Proposed Binding of VCp2X2 to DNA
VCp2 have loose interaction with PO4 Group
VCp2(bpy) dissociates differently than VCp2Cl2
VCp2(bpy) binds DNA differently leading to a
different mode of activity?
PO
Anticancer Activity of VCp2(bpy)
 Many VCp2(chelator) compounds synthesized in 1960-1975.
 No Reported Biological Activity
 First Reported Synthesis of VCp2(byp) compound
 VCp2(byp) has high efficacy with low dosage (Unexpected Result)
In Vitro Cytotoxicity of Vanadocene
Compounds Against Human Cancer
PO
Claimed Invention: VCp2(bpy)OTf2
Patentability of Claim 5
 In certain tumors, VCp2Cl2 is the only Metal-Cp2Cl2
complex to demonstrate anti-cancer activity.
 This unexpected result implies a new reactivity for V
complexes toward these cancer and nullifies any previous
assumptions about other ligands.
 Synthesis of VCp2(bpy)OTf2 was previously unreported
in the literature
VCp2(bpy)OTf2 shows high efficacy of cancer cell death
with low doses compared to other VCp2(chelator) ligands.
AI
Claimed Invention: VCp2(bpy)OTf2
Invalidity of Claim 5: Obviousness
Synthesis of VCp2(bpy)OTf2 was obvious to POSITA
from published analogous synthesis of TiCp2(bpy)OTf2.
Substitution of V for Ti is common in studies of
metallocene complexes, so there is motivation to combine
in the prior art.
TiCp2(bpy)OTf2 showed anti-cancer activity, so it is not
an unexpected result for VCp2(bpy)OTf2 to show anticancer activity.
AI
Synthesis of VCp2(bpy)OTf2
 2 step synthesis of TiCp2(bpy)OTf2
published in 1986
(J. Organometallic Chem. 1986, 302, 193.)
 Patent acknowledges using
“modified” TiCp2(bpy)(OTf2)2
synthesis
 VCp2X2 and TiCp2X2 are
commonly made using the same
procedure, as would be known by
POSITA.
 VCp2Cl2 and TiCp2Cl2 are
commercially available.
TiCp2(bpy)(OTf2)2
AI
Metallocenes with Antitumor Activity
X
M
X
Cl
Ti
Br
Ti
Cl
Br
Cl
V
Cl
Cl
Cl
N3
NCS
Mo
Br
N3
Nb
NCS
Br
Mo
N3
NCS
Nb
Br
Cl
Mo
N3
V
NCS
Br
Nb
N3
NCS
V
Br
Cl
N3
Ti
NCS
Br
V
Nb
NCS
Ti
N3
Mo
NCS
Examiner failed to take into account prior art for
VCp2X2 compounds when considering application.
N3
AI
Activity Against Fluid Ehrlich Ascites Tumor
Cl
Cl
Ti
V
Cl
Optimum Dose Range = 40 – 60 mg/kg
Cure Rate = 100%
Cl
Optimum Dose Range = 80 – 90 mg/kg
Cure Rate = 100%
N
Ti
N
V
N
Optimum Dose Range = 140 – 220 mg/kg
Cure Rate = 100%
N
Optimum Dose Range = ?
Cure Rate = ?