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Boron-Based 4-Hydroxytamoxifen Bioisosteres for Treatment of De Novo Tamoxifen Resistant Breast Cancer

Boron-Based 4-Hydroxytamoxifen Bioisosteres for Treatment of De Novo Tamoxifen Resistant Breast Cancer

Quan Jiang, Qiu Zhong, Qiang Zhang, Shilong Zheng, Guangdi Wang

ACS Med Chem Lett. 2012 Apr 6;3(5):392-396.

PMID: 23864928

Abstract:

Tamoxifen remains the first line therapy for estrogen receptor positive (ER+) breast cancer. However, polymorphisms of the gene encoding P450 2D6 could result in no protein expression or no CYP2D6 enzymatic activity and may significantly reduce the benefit of the hormone therapy. To address this issue, we designed and synthesized three 4-hydroxytamoxifen bioisosteres utilizing a boron-aryl carbon bond that can be oxidized under physiological conditions to yield 4-hydroxytamoxifen. We show that the bioisosteres inhibit the growth of two ER+ breast cancer cell lines, MCF-7 and T47D, with potencies comparable to or greater than that of 4-hydroxytamoxifen. We further demonstrate that after incubation with breast cancer cells, the majority of the bioisosteres has been converted to 4-hydroxytamoxifen. Our study suggests that boron-based 4-hydroxytamoxifen bioisosteres may be an effective therapeutic remedy for intrinsic tamoxifen resistance in breast cancer patients deficient in CYP2D6 metabolism.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP68392358	4-Hydroxytamoxifen		68392-35-8	Price

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