FIELD

The field pertains to synthesis of cytotoxic compounds that are analogs of mycalolides.

BACKGROUND

Actin is recognized as a strategic target for anticancer agents, although many of the naturally occurring agents are too complex and toxic to be utilized as drugs. Actin is a 43-kDa globular protein (G-actin) that can reversibly polymerize into helical filaments (F-actin), which form a three-dimensional network inside eukaryotic cells. G-actin is an ATPase that can be divided into four subdomains, where hydrolysis of ATP occurs deep within a cleft that separates subdomains 2 and 4. ATP hydrolysis is associated with G-actin's propensity to assemble into, or remain part of, F-actin polymers, such that the transition to the ADP-bound form reduces G-actin's filament-forming ability to permit F-actin depolymerization. The reversible polymerization of G-actin into F-actin in the cytosol, known as ‘cytoskeleton remodeling’, is critical for cytokinesis, cell division, vesicle and organelle movement, cell signaling, and maintenance of cell shape. Dynamic remodeling of actin filaments in the cytosol also drives shape changes, cell locomotion, and chemotactic migration that are vital to tissue development, wound healing, neuron migration, immune responses, and maintenance of homeostasis. However, these activities of actin can become aberrantly regulated in cancer, particulary those that spread to other sites (metastasis). It is postulated that anticancer drugs that interfere with actin may be able to disrupt tumor cell division, as well as tumor cell migration and invasion events that lead to metastatic disease. Hence, there is a need to develop new anticancer drugs that employ actin as their strategic target, which would constitute a new approach to chemotherapy.

SUMMARY

According to one aspect of the invention there is provided a compound of structural Formula (1),


wherein R1is independently H, —C(═O)R, —C(OR)(R)(R), —C(═O)NR2R3, —S(O2)NR, —P(═O)(OR)2, aliphatic and/or aryl moiety, and R, R2, and R3are independently an aliphatic moiety and/or aryl moiety that is substituted or unsubstituted and optionally includes one or more heteroatoms.

According to another aspect of the invention there is provided a pharmaceutical composition, comprising an effective amount of a compound of Formula (1). In one embodiment, the compound of structural formula (1) of the above aspects is compound 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 11, 12, MA-02-058, MA-02-047, MA-02-044, or MA-02-046 as shown in Table 1, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle.

According to another aspect of the invention there is provided a method of treating and/or mitigating cancer, comprising administering to a subject a pharmaceutical composition comprising a compound of Formula (1). In one embodiment, the cancer is metastatic cancer, such as, for example, breast cancer, ovarian cancer, melanoma, colorectal cancer, kidney cancer, cervical cancer, testicular cancer, or liver cancer. In one embodiment, the compound of Formula (1) inhibits actin.

According to another aspect of the invention there is provided a pharmaceutical composition for the treatment and/or mitigation of cancer, comprising an effective amount of a compound of Formula (1). In one embodiment, the pharmaceutical composition includes a compound of Formula (1) such as compound 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 11, 12, MA-02-058, MA-02-047, MA-02-044, or MA-02-046 as shown in Table 1, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of the above embodiments or aspects, further comprising a pharmaceutically acceptable vehicle. In one embodiment, the pharmaceutical composition is for the treatment and/or mitigation of cancer. In one embodiment, the cancer is metastatic cancer. In one embodiment, the cancer is breast, ovarian, lung, or pancreatic cancer.

According to another aspect of the invention there is provided a pharmaceutical composition for suppressing metastatic cancer cell motility and survival, comprising a pharmaceutical composition as defined in any one of above embodiments or aspects, and a pharmaceutically acceptable vehicle. In one embodiment, the metastatic cancer is breast cancer, ovarian cancer, lung cancer, pancreatic cancer, melanoma, colorectal cancer, kidney cancer, cervical cancer, testicular cancer, or liver cancer. In one embodiment, the pharmaceutical composition further comprising one or more antineoplastic agent(s). In one embodiment, the pharmaceutical composition further comprises a protein or a glycosaminoglycan. In one embodiment, the protein is an antibody, hemoglobin, alphafeto-protein, fibrinogen, or serum albumin. In one embodiment, the glycosaminoglycan comprises hyaluronic acid.

According to another aspect of the invention there is provided a method of treating and/or mitigating cancer, a cell proliferation disorder, or an actin-related disorder, comprising administering to a subject a pharmaceutical composition comprising a compound of Formula (1). In one embodiment, the the cancer is metastatic cancer. In one embodiment, the metastatic cancer is breast cancer, ovarian cancer, lung cancer, pancreatic cancer, melanoma, colorectal cancer, kidney cancer, cervical cancer, testicular cancer, or liver cancer. In one embodiment, the compound of Formula (1) inhibits actin. In one embodiment, the compound of Formula (1) is compound 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 11, 12MA-02-058, MA-02-047, MA-02-044, or MA-02-046 of Table 1.

According to another aspect of the invention there is provided a method of inhibiting actin in a subject in need thereof, comprising administering to the subject the compound of Formula (1). In one embodiment of this aspect, the subject has inflammatory lung disease. In one embodiment of this aspect, sputum viscosity is reduced. In one embodiment, the actin-related disorder comprises accumulation of actin in cell nuclei. In one embodiment, the actin-related disorder comprises malaria.

According to another aspect of the invention there is provided a method of reducing actin released into circulation upon cellular damage, comprising administering the pharmaceutical composition to a subject in need thereof. In one embodiment of this aspect, the the cellular damage was caused by stroke, or an adverse cardiovascular problem.

According to another aspect of the invention there is provided a method of suppressing tumor growth, metastasis, or both, comprising administering a pharmaceutical composition as defined in any of the above embodiments or aspects, to a subject in need thereof.

According to another aspect of the invention there is provided a method of treating an actin-related disorder, comprising administering a pharmaceutical composition as defined in any of the above embodiments, to a subject in need thereof. In one embodiment, the the actin-related disorder comprises sputum viscosity in a subject with inflammatory lung disease. In one embodiment, the actin-related disorder comprises accumulation of actin in cell nuclei. In one embodiment, the actin-related disorder comprises malaria.

According to another aspect of the invention there is provided a method of reducing actin released into circulation upon cellular damage, comprising administering a pharmaceutical composition as defined in any one of the above embodiments to a subject in need thereof. In one embodiment, the cellular damage was caused by stroke, or an adverse cardiovascular problem.

According to another aspect of the invention there is provided use of a compound of Formula (1) for preparation of a medicament for treating and/or mitigating one or more of cancer, actin-related disorder, malaria, inflammatory lung disease, stroke, or an adverse cardiovascular problem.

