# US 11,304,958 B2 · Multidentate phenanthridine-containing ligand frameworks and their planar monofunctional platinum complexes for cancer treatment

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- Number: US 11,304,958 B2
- Document ID: US11304958B2
- Status: Granted
- Kind: B2
- Application number: 17/041,592
- Filed: 2019-05-24
- Published: 2021-02-25
- Granted: 2022-04-19
- Earliest claimed: 2018-05-25
- Assignees: University of Manitoba
- Applicants: University of Manitoba
- Inventors: David E. Herbert; Issiah B. Lozada; Bin Huang; Yaorong Zheng; Zihan Qiu
- Web page: https://patentgrep.com/patent/US11304958B2

## CPC

- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- C07D 221/12: Phenanthridines
- A61P 35/00: Antineoplastic agents
- C07F 15/0093: {without a metal-carbon linkage}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Described herein is the development of synthetic routes to produce a wide variety of substituted phenanthridines, specifically, multidentate phenanthridine-containing ligand frameworks capable of anchoring to Pt via more than one binding site and with the phenanthridinyl moiety co-planar to the coordination plane of Pt. The multidentate chelation is designed to attenuate the reactivity of the platinum complex in vivo, and ultimately help mitigate side effects. In addition, the geometry of phenanthridine binding to the metal centre is altered compared to in phenanthriplatin, thanks to the constraints of the ligand geometry. By enforcing coplanar binding with the metal's square planar coordination plane, these compounds exhibit altered modes of activity, and should hence enhance/change the spectrum of activity of our prodrug candidates compared with phenanthriplatin.

## Claims

### Claim 1

An anti-cancer compound comprising a compound of formula (I):
wherein:
X is a halide, a nitrate, a carboxylate or an anionic ligand;
R1-R8 are individually H, tBu, CH3, CF3, Cl, Br, F, C(O)H or OR, where R is an alkyl or aryl; and
R9 and R19 are individually H, CF3 or CH3.

### Claim 2 (depends on 1)

The anti-cancer compound according to claim 1 wherein R1-R6 and R8═H, R7═CF3 or tBu, and R9-R10=cH3.

### Claim 3 (depends on 1)

The anti-cancer compound according to claim 1 wherein R1═R7═CH3, R2-6═R8═H.

### Claim 4 (depends on 1)

The anti-cancer compound according to claim 1 wherein R1-8═H.

### Claim 5 (depends on 1)

The anti-cancer compound according to claim 1 wherein R7═C(═O)H (aldehyde), R1-6═R8═H.

### Claim 6 (depends on 1)

The anti-cancer compound according to claim 1 wherein the anti-cancer compound is selected from the group consisting of: R7=Su; R7═CF3; R7═CH3; R1═CH3, ═CH3, R10═CH3; R1═H, R7═R10═CF3; and R1═H, R7═CF3, R10═CF3.

### Claim 7 (depends on 1)

A method of modifying a compound of formula (I) as set forth in claim 1 comprising:
providing a compound of formula (I) wherein at least one of R1-R8 is CH3; and
subjecting the compound to oxidizing conditions such that the at least one CH3 is converted to C(O)H.

### Claim 8 (depends on 7)

The method according to claim 7 further comprising, following subjection to the oxidizing conditions, converting the C(O)H to an amide group, a carboxylic acid group or an ester group.

### Claim 9 (depends on 8)

The method according to claim 8 further comprising, following conversion, conjugating targeting tag to the compound via the amide group, the carboxylic acid group or the ester group.

### Claim 10 (depends on 9)

The method according to claim 9 wherein the targeting tag is a protein, a peptide tag, a DNA molecule, an oligonucleotide or an siRNA.

### Claim 11 (depends on 1)

A method of treating cancer comprising administering to an individual in need of such treatment an effective amount of an anti-cancer compound as set forth in claim 1.

### Claim 12 (depends on 11)

The method according to claim 11 wherein the compound is co-administered with a second anti-cancer drug.

### Claim 13 (depends on 12)

The method according to claim 12 wherein the second anti-cancer drug is selected from the group consisting of: fluorouracil, etoposide, paclitaxel, leucovorin and capecitabine.

### Claim 14 (depends on 11)

The method according to claim 11 wherein the cancer is selected from the group consisting of anal cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, prostate cancer, testicular cancer, thymic cancer, neuroendocrine cancer, soft tissue sarcoma, breast cancer, endometrial cancer, thyroid cancer, melanoma and colorectal cancer.