EP-4735535-A2 - COMPOUNDS INCLUDING A WATER-SOLUBILIZATION MOTIF AND METHODS OF USE THEREOF

Abstract

Described herein are compounds that include a tetrapyrrole macrocycle and a water solubilizing group that is attached to the tetrapyrrole macrocycle along with methods of using the same.

Inventors

• Wu, Zhiyuan
• CAO, Phuong-Lien Doan
• LINDSEY, JONATHAN S.

Assignees

• North Carolina State University

Dates

Publication Date

20260506

Application Date

20240625

Claims (1)

1. Attorney Docket No.5051.1014.WO THAT WHICH IS CLAIMED IS: 1. A compound comprising: a tetrapyrrole macrocycle; and a water solubilizing group attached to the tetrapyrrole macrocycle, wherein the water solubilizing group comprises a hydroxyl, carboxylic acid, and/or a methoxy group. 2. The compound of claim 1, wherein the water solubilizing group comprises the carboxylic acid. 3. The compound of claim 1, wherein the water solubilizing group comprises the methoxy group. 4. The compound of any one of claims 1-3, wherein the hydroxyl, carboxylic acid, or methoxy group is a terminal hydroxyl, terminal carboxylic acid, or terminal methoxy group. 5. The compound of any one of claims 1-4, wherein the tetrapyrrole macrocycle is a porphyrin, chlorin, isobacteriochlorin, or bacteriochlorin. 6. The compound of any one of claims 1-5, wherein the water solubilizing group comprises a polyethylene glycol (PEG) group, sulfonate, ammonium, carboxylate, betaine, phosphate, phosphonate, amino acid residue, glycoside and/or peptide, optionally wherein the water solubilizing group comprises a carboxy-terminated PEG group (e.g., carboxy-terminated PEG group) and/or an amine-terminated group. 7. The compound of any one of claims 1-6, wherein the water solubilizing group comprises a glycoside that is a glucoside, galactoside, glucuronide, or galacturonide. 8. The compound of any one of claims 1-7, wherein the water solubilizing group comprises a PEG group, optionally wherein the PEG group comprises 1 to 24 PEG units. 56 Attorney Docket No.5051.1014.WO 9. The compound of claim 8, wherein the PEG group has a structure of: –(OCH 2 CH 2 ) n1 X(CH 2 ) m1 Y, wherein: n1 is an integer of 1 to 24; X is -O-, -S-, -NH-, or absent; m1 is 0 or an integer of 1 to 10; and Y is -H, -CH3, -C(O)ORx, -PO3H2, or -SO3H, wherein Rx is H or a C1-C5 alkyl. 10. The compound of any one of claims 1-9, wherein the water solubilizing group comprises a swallowtail group. 11. The compound of claim 10, wherein the swallowtail group has a structure of: -CH((CH 2 ) n2 (C(O)O) m2 (CH 2 ) p2 Y) 2 , wherein: n2 is an integer of 1 to 20; m2 is 0 or 1; p2 is 0 or an integer of 1 to 10; and Y is -H, -OH, -SH, -NH2, -NHCH3, -OCH3, -PO3H2, -SO3H, or -C(O)OH, optionally wherein Y is -OCH 3 or -C(O)OH. 12. The compound of claim 10, wherein the swallowtail group has a structure of: -CH((CH 2 ) n3 (OCH 2 CH 2 ) m3 X(CH 2 ) p3 Y) 2 , wherein: n3 is an integer of 1 to 20; m3 is 0 or 1 to 24; X is -O-, -S-, -NH-, or absent; p3 is 0 or an integer of 1 to 10; and Y is -H, -CH3, -C(O)OH, -PO3H2, or -SO3H, optionally wherein Y is -C(O)OH. 13. The compound of claim 10, wherein the swallowtail group has a structure of: -CH((CH2)n4(C(O)NH)(CH2)m4(OCH2CH2)p4X(CH2)q4Y)2, 57 Attorney Docket No.5051.1014.WO wherein: n4 is an integer of 1 to 20; m4 is 1 to 20; p4 is 0 or an integer of 1 to 24; X is -O-, -S-, -NH-, or absent; q4 is 0 or an integer of 1 to 10; and Y is -H, -CH 3 , -C(O)OH, -PO 3 H 2 , or -SO 3 H, optionally wherein Y is -C(O)OH. 14. The compound of any one of claims 1-13, wherein the compound has a molecular weight of about 400 Daltons to about 500, 1000, 2500, or 5000 Daltons. 15. The compound of any one of claims 1-14, wherein the compound has a water solubility of at least 0.1 mg/mL. 16. The compound of any one of claims 1-15, wherein the compound has a logarithm of partition coefficient (LogP) of less than 0, optionally wherein the compound has a LogP of -0.25 to about -5. 17. The compound of any one of claims 1-16, wherein the compound has a 1-octanol to aqueous composition partitioning ratio in a range of about 1:1.5 or 1:2 to about 1:100 or 1:100,000 (1-octanol : aqueous composition), wherein the aqueous composition is deionized water or phosphate buffered saline at pH 7.4, optionally wherein the PBS is about 0.1M. 18. The compound of any one of claims 1-17, wherein the compound comprises two or more (e.g., 3, 4, 5, 6, or more) water solubilizing groups. 19. The compound of any one of claims 1-18, wherein the water solubilizing group is attached at the perimeter of the tetrapyrrole macrocycle. 58 Attorney Docket No.5051.1014.WO 20. The compound of any one of claims 1-19, wherein the water solubilizing group is attached at the 5-position and/or 15-position of the tetrapyrrole macrocycle (e.g., porphyrin, bacteriochlorin, isobacteriochlorin, or chlorin). 21. The compound of claim 20, wherein the water solubilizing group comprises a first water solubilizing group and a second water solubilizing group, and the first water solubilizing group is attached at the 5-position of the tetrapyrrole macrocycle and the second water solubilizing group is attached at the 15-position of the tetrapyrrole macrocycle. 22. The compound of claim 20, wherein the water solubilizing group comprises a first water solubilizing group, a second water solubilizing group and a third water solubilizing group, and the first water solubilizing group is attached at the 5-position of the tetrapyrrole macrocycle, the second water solubilizing group is attached at the 10-position of the tetrapyrrole macrocycle, and the third water solubilizing group is attached at the 15-position of the tetrapyrrole macrocycle. 23. The compound of any one of claims 1-22, wherein the water solubilizing group is attached at a meso-position or at a beta-position of the tetrapyrrole. 24. The compound of any one of claims 1-23, further comprising a first linker, wherein the first linker is attached to the tetrapyrrole macrocycle and the water solubilizing group. 25. The compound of any one of claims 1-24, wherein the tetrapyrrole macrocycle comprises a metal, optionally wherein the metal is copper, zinc, iron, magnesium, gold, aluminum, silicon, palladium, indium, tin, or platinum. 26. The compound of any one of claims 1-25, wherein the tetrapyrrole macrocycle comprises a radionuclide, optionally wherein the radionuclide is 64 Cu, 67 Cu, 44 Sc, 47 Sc, 67 Ga, 68 Ga, 89 Zr, 99m Tc, 111 In, 177 Lu, 51 Mn, 52g Mn, 52m Mn, 86 Y, 62 Zn, 123 I, 125 I, 131 I, 211 At, 18 F, or 57 Co, optionally wherein the radionuclide is a copper radionuclide (e.g., 64 Cu or 67 Cu). 59 Attorney Docket No.5051.1014.WO 27. The compound of any one of claims 1-26, wherein the tetrapyrrole macrocycle has a structure of Formula Ia, Formula Ib, Formula Ic, or Formula Id: , , 60 Attorney Docket No.5051.1014.WO , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from the group consisting of a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, aryloxy, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, 61 Attorney Docket No.5051.1014.WO heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, aminoacyloxy, hydrophilic groups, linking groups, bioconjugatable groups, surface attachment groups, targeting groups, and the water solubilizing group, each of which may optionally be substituted; or R 1 and R 2 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; or R 2 and R 3 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; or R 3 and R 5 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; or R 4 and R 5 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; or R 4 and R 7 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; or R 7 and R 8 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; or R 9 and R 10 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; or or R 10 and R 11 together represent a fused aromatic or heteroaromatic ring system that is substituted or unsubstituted; and M 1 , if present, is a metal (e.g., zinc, magnesium, gold, aluminum, silicon, palladium, indium, tin, copper, or platinum) or a radionuclide (e.g., 64 Cu, 67 Cu, 44 Sc, 47 Sc, 67 Ga, 68 Ga, 89 Zr, 99m Tc, 111 In, 177 Lu, 51 Mn, 52g Mn, 52m Mn, 86 Y, 62 Zn, 57 Co, 123 I, 125 I, 131 I, 18 F, or 211 At); and W is N, O, S, Se, or CH, wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is the water solubilizing group or is substituted with the water solubilizing group. 62 Attorney Docket No.5051.1014.WO 28. The compound of any one of claims 1-27, further comprising a targeting agent (e.g., 1, 2, 3, 4, or more targeting agent(s)), optionally wherein the targeting agent is a cancer target agent and/or optionally wherein the compound comprises at least two targeting agents. 29. The compound of claim 28, further comprising a second linker, wherein the second linker is attached to the tetrapyrrole macrocycle and the targeting agent. 30. A method of diagnosing a disease or disorder in a subject, the method comprising: administering a compound of any one of claims 1-29 to the subject, thereby diagnosing the disease or disorder in the subject. 31. The method of claim 30, wherein the disease or disorder is cancer. 32. A method of treating a subject in need thereof, the method comprising: administering a compound of any one of claims 1-31 to the subject, thereby treating the subject. 33. The method of any one of claims 30-32, wherein the administering comprises intravenously administering the compound to the subject. 34. The method of any one of claims 30-33, further comprising imaging the subject and/or detecting the radionuclide, optionally wherein the imaging and/or detecting is performed using Magnetic Resonance Imaging (MRI), positron emission tomography (PET), and/or Computed Tomography (CT) (e.g., single-photon emission computed tomography (SPECT)). 35. The method of any one of claims 30-34, further comprising detecting the compound and/or radionuclide in the subject. 36. The method of any one of claims 30-35, wherein the subject has or is suspected to have cancer. 63

Description

Attorney Docket No.5051.1014.WO COMPOUNDS INCLUDING A WATER-SOLUBILIZATION MOTIF AND METHODS OF USE THEREOF STATEMENT OF PRIORITY This application claims the benefit of and priority to U.S. Provisional Application Serial Number 63/511,202, filed June 30, 2023, the contents of which are hereby incorporated by reference as if recited in full herein. GOVERNMENT SUPPORT This invention was made with government support under grant number 2136700 awarded by the National Science Foundation. The government has certain rights in the invention. FIELD The present invention concerns compounds that include a water-solubilization motif and methods of use thereof. BACKGROUND Therapeutic agents can be hydrophobic, which can create issues with their use such as in regard to renal clearance of the therapeutic agent following administration to a subject. For example, a key issue in cancer therapy is renal clearance of unbound radionuclides. Accordingly new compounds and methods are desired. SUMMARY One aspect of the present invention is directed to a compound comprising a tetrapyrrole macrocycle and a water solubilizing group that is attached to the tetrapyrrole macrocycle, wherein the water solubilizing group comprises a hydroxyl, carboxylic acid, and/or a methoxy group. A further aspect of the present invention is directed to a method of diagnosing a disease or disorder in a subject, the method comprising: administering a compound of the present invention to the subject, thereby diagnosing the disease or disorder in the subject. 1   Attorney Docket No.5051.1014.WO Another aspect of the present invention is directed to a method of treating a subject in need thereof, the method comprising: administering a compound of the present invention to the subject, thereby treating the subject. It is noted that aspects of the invention described with respect to one embodiment, may be incorporated in a different embodiment although not specifically described relative thereto. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination. Applicant reserves the right to change any originally filed claim and/or file any new claim accordingly, including the right to be able to amend any originally filed claim to depend from and/or incorporate any feature of any other claim or claims although not originally claimed in that manner. These and other objects and/or aspects of the present invention are explained in detail in the specification set forth below. Further features, advantages and details of the present invention will be appreciated by those of ordinary skill in the art from a reading of the figures and the detailed description of the preferred embodiments that follow, such description being merely illustrative of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS Fig.1 shows 1H NMR spectra in CDCl3 at room temperature of zinc porphyrins Zn2 (top panel) and Zn6 (bottom panel). Peak assignments: (a) The resonance of the triazolyl–H; (b) The resonance of the protons of the –OCH2– linking the meso-aryl and triazole moieties. All other peaks derive from the PEG chains. Fig.2 depicts the crystal structure of compound Zn5 (crystallized from THF at –20 °C). Disorder is omitted for clarity. Fig.3 is a graph showing the absorption spectra of compound 6 in PBS at room temperature. Fig.4 is a graph showing the absorption spectra of compound Cu6 in PBS at room temperature. Fig.5 is a graph showing the absorption spectra of compound 8 in PBS at room temperature. Fig.6 is a graph showing the absorption spectra of compound 11 in PBS at room temperature. 2   Attorney Docket No.5051.1014.WO Fig.7 depicts the wide conformational motion available in the 3,5-disubstituted aryl porphyrin (top panel) versus limited motion for the 2,6-disubstituted aryl porphyrin (bottom panel). DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS The present invention is now described more fully hereinafter with reference to the accompanying drawings, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as