Synthesis of (aryloxyacetylamino)-isonicotinic/nicotinic acid analogues as potent hypoxia-inducible factor (HIF)-1α inhibitors

Boovanahalli, Shanthaveerappa K.; Jin, Xuejun; Jin, Yinglan; Kim, Jin Hwan; Dat, Nguyen Tien; Hong, Young-Shick; Lee, Jeong Hyung; Jung, Sang‐Hun; Lee, Kyeong; Lee, Jun Young

doi:10.1016/j.bmcl.2007.09.005

Cited by 28 publications

(21 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In an assay that measured hypoxia-induced HIF-1a activation in two cancer cell lines, 25 was at least 6-fold times more active than the des-adamantyl analogue [118]. While structureeactivity relationships showed that the adamantyl group was essential in maintaining activity as an HIF-1a inhibitor, the exact role of the adamantyl group was not clear [118,119]. Compound 25a was twofold more active than 25 in these assays and has progressed to further in vitro and in vivo studies.…”

Section: Anticancer Agentsmentioning

confidence: 95%

The many faces of the adamantyl group in drug design

Liu

Obando

Liao

et al. 2011

European Journal of Medicinal Chemistry

268

172

View full text Add to dashboard Cite

Section: Anticancer Agentsmentioning

confidence: 95%

The many faces of the adamantyl group in drug design

Liu

Obando

Liao

et al. 2011

European Journal of Medicinal Chemistry

268

172

View full text Add to dashboard Cite

“…Among the nicotinic derivatives, only the nicotinic methyl ester maintained some activity in the Hep3B cell line, with an IC 50 value of 5.9 μM. Acids and amides were not active, exhibiting IC 50 values >30 μM . There are some inconsistencies in the activity of these derivatives among different cell lines.…”

Section: Adamantyl‐based Inhibitorsmentioning

confidence: 99%

“…Similar to LW6, the isonicotinic ester 5a, acid 5b, and isonicotinamide 5c derivatives exhibited similar or better potency in the Hep3B cell line with IC 50 values of 1.2, 1.0, and 3.1 M, respectively, whereas bulkier amides were less active or lost their activity completely (IC 50 => 30 M for 5d, 3.4 M for 5e, and >30 M for 5f, Table 3). Among the nicotinic derivatives, only the nicotinic methyl ester maintained some activity in the Hep3B cell line, with an IC 50 value of 5.9 M. Acids and amides were not active, exhibiting IC 50 values >30 M. 20,21 There are some inconsistencies in the activity of these derivatives among different cell lines. These inconsistencies may arise due to the different genetic backgrounds and molecular lesions of different cell lines or the physiochemical properties of these derivatives.…”

Section: Adamantyl-based Inhibitorsmentioning

confidence: 99%

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Bhattarai

Lee

2017

Medicinal Research Reviews

Self Cite

View full text Add to dashboard Cite

Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia-inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF-1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF-1 inhibitors. In this review, we will summarize the structure-activity relationship of ten different chemotypes reported to be HIF-1 inhibitors in the last decade (2007-2016), their mechanisms of action for HIF-1 inhibition, progress in the way of target-specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF-1 inhibitors will provide decent information in the design and development of future inhibitors.

show abstract

“…Pyridine moiety serves as a good bioisosteric replacement for phenyl portion and the position of nitrogen atom at pyridine ring is important for potency. 2) as to the adamantyl phenyl ring A, the presence of the adamantyl substituent, or an equivalent, on ring A is essential for effective inhibition of HIF-1 under hypoxia and the replacement of adamantyl group with a substituted phenyl ring would cause a significant loss of activity [171,172]. Future directions of this class of HIF-1 inhibitors are to complement the framework of SARs for rational drug design and to promote the available preclinical results of these promising analogues to clinical trials.…”

Section: (Aryloxyacetylamino)benzoic Acid Analog-uesmentioning

confidence: 99%

Cancer Therapeutic Agents Targeting Hypoxia-Inducible Factor-1

Wang¹,

Zhou

2011

CMC

View full text Add to dashboard Cite

The discovery of hypoxia-inducible factor-1 has led to a rapidly increasing understanding of the molecular mechanism of tumor hypoxia in the past two decades. Today it is generally accepted that HIF-1 plays a pivotal role in the cellular response to tumor hypoxia which represents a major obstacle to the success of radiotherapy and chemotherapy. Meanwhile, many details involved in the expression, accumulation and transactivation of HIF-1 have been well elucidated. Targeting HIF-1 has become a novel and efficient strategy for cancer therapy and a number of agents have been developed aiming to suppress HIF-1. This review will concisely introduce the general knowledge on the molecular biology of HIF-1 and possible targets along the HIF-1 pathway. Moreover, a number of compounds reported with anti-HIF-1 activity are included and mainly classified as direct and indirect inhibitors based on their different modes of action. While direct HIF-1 inhibitors prevent HIF-1 from transactivation, DNA binding and subsequently initiating transcriptional activity, indirect HIF-1 inhibitors generally block the transcription or translation of HIF-1α or promote the degradation of HIF-1α protein. According to different structural features, direct HIF-1 inhibitors are divided into several groups: polyamides, quinols and naphthoquinone spiroketal analogues, shikonin derivatives, epidithiodiketopiperazines, and two representative drugs: echinomycin and bortezomib. In the same way, indirect inhibitors comprise the following classes: polyphenols, benzoazaheterocycles, rapamycins, camptothecins, geldanamycins, (aryloxyacetylamino)benzoic acid analogues, 2-methoxyestradiol and analogues, hydroxamic acid compounds and others. The rest with mechanism still not so clear would also be listed and introduced, with an emphasis on the marinederived natural products. The in vitro and/or in vivo activities of these compounds and their mechanisms of HIF-1 inhibition would be discussed and the SARs of unique structural types of HIF-1 inhibitors will be briefly concluded.

show abstract

Synthesis of (aryloxyacetylamino)-isonicotinic/nicotinic acid analogues as potent hypoxia-inducible factor (HIF)-1α inhibitors

Cited by 28 publications

References 33 publications

The many faces of the adamantyl group in drug design

The many faces of the adamantyl group in drug design

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Cancer Therapeutic Agents Targeting Hypoxia-Inducible Factor-1

Contact Info

Product

Resources

About