Date of Award

12-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John D. Chisholm

Keywords

3AC, aminosteroids, Apicularen A, Maoecrystal V, SHIP inhibitors

Subject Categories

Chemistry

Abstract

This dissertation involves work both on the syntheses of small molecules with potential therapeutic applications and synthetic studies on natural products with unusual core skeletons.

The first part of this work involves the synthesis, design, and biological evaluation of aminosteroids as inhibitors for the SH2-containing inositol phosphatase 1 (SHIP1). SHIP1, a 145 kDa protein, is involved in regulating the formation of new blood cells. High- throughput screening identified several SHIP inhibitors including NSC23922, a mixture of 3a- and 3β-aminocholestane. Both 3a- and 3β-aminocholestane were synthesized from dihdyrocholesterol and the 3a- form was verified as SHIP1 inhibitor. Comparison of the 3a- and 3β-aminocholestane showed that the former was the more active form. Further biological studies on 3a-aminocholestane (3AC) showed similar biological activities observed with NSC23922 such as rapid and increased recovery of blood components in myelosuppressed hosts, increased myeloid immunoregulatory (MIR) cells, and reduced survival of cancer cells that express SHIP1. Synthetic studies were undertaken to determine which portions of the aminosteroid SHIP1 inhibitors are important for its biological activity and to improve the water solubility of the aminosteroid. This led to the synthesis of androsterone based derivatives with greater potency and solubility. Syntheses of other derivatives with additional polar functional group on ring A were also explored. While these molecules showed better SHIP1 inhibitory activity compared with 3AC, many showed significant inhibition of SHIP2, suggesting that not all aminosteroids are SHIP1 selective inhibitors. Some known SHIP1 activators were also pursued, as these molecules would be useful for validation of screening techniques and biological assays. The reported structure containing a sulfone moiety was problematic to test due to its low solubility in water or dimethyl sulfoxide (DMSO).

The second part of this work involves the synthesis of thiophene based SHIP2 inhibitors AS1949490 and AS1938909 and some analogs of these molecules. SHIP2 inhibitors have potential therapeutic application to breast cancer treatment since overexpression of SHIP2 in breast cancer supports cell proliferation while its suspension retards cancer growth. In addition, the inhibitory activities against SHIP1 of these molecules were evaluated. Although both molecules did not show any inhibitory potency against SHIP1, both molecules showed comparable SHIP2 inhibitory activity. The analogs of AS1949490, particularly the 4-bromobenzyl and 4-methoxybenzyl analogs showed almost a 3-fold increase in potency against SHIP2 compared to the parent molecule.

The third part of this work involved studies towards the synthesis of apicularen A. Apicularen A is a macrosalicylic natural product isolated from the myxobacterial genus Chondromyces and showed potent cytotoxic activity against several cancer cell lines. A synthetic route towards apicularen A was investigated featuring an intramolecular Diels-Alder reaction using an aldehyde as a dienophile as the key step.

The fourth part of this work involves the synthetic studies on maoecrystal V. Maoecrystal V is a diterpenoid containing a unique kaurane skeleton. This compound was isolated from the leaves of Isodon eriocalyx and shows selective cytotoxic activity towards HeLa cells having an IC50 of 0.02 μg/mL. The syntheses of the tricylic core of this molecule were explored using a Diels-Alder reaction followed by a subsequent annulation reaction.

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