302941-54-4Relevant academic research and scientific papers
COMPOSITIONS AND METHODS FOR ADOPTIVE CELL THERAPY
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Paragraph 0394; 0415; 0416, (2019/01/17)
Provided herein are compositions and methods for adoptive cell therapy comprising engineered immune cells that express an antigen-targeted chimeric antigen receptor and a prodrug converting enzyme for the treatment of inflammation, inflammatory diseases, or pathogenic infections.
COMPOSITIONS AND METHODS FOR ADOPTIVE CELL THERAPY FOR CANCER
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Paragraph 0417; 0418, (2019/01/17)
Provided herein are compositions and methods for adoptive cell therapy comprising engineered immune cells that express a tumor antigen-targeted chimeric antigen receptor and a prodrug converting enzyme.
Synthesis and biological evaluation of novel 10-substituted-7- Ethyl-10-hydroxycamptothecin (SN-38) prodrugs
Mo, Zhou,Liu, Meixia,He, Xinhua,Yao, Yishan,Fan, Shiyong,Zhang, Ping,Shi, Weiguo,Zhong, Bohua,Yu, Hong,Wu, Di
, p. 19718 - 19731 (2015/02/05)
In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 ( 3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.
Synthesis of Urea-Based Inhibitors as Active Site Probes of Glutamate Carboxypeptidase II: Efficacy as Analgesic Agents
Kozikowski, Alan P.,Zhang, Jiazhong,Nan, Fajun,Petukhov, Pavel A.,Grajkowska, Ewa,Wroblewski, Jarda T.,Yamamoto, Tatsuo,Bzdega, Tomasz,Wroblewska, Barbara,Neale, Joseph H.
, p. 1729 - 1738 (2007/10/03)
The neuropeptidase glutamate carboxypeptidase II (GCPII) hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to liberate N-acetylaspartate and glutamate. GCPII was originally cloned as PSMA, an Mr 100 000 type II transmembrane glycoprotein highly expressed in prostate tissues. PSMA/GCPII is located on the short arm of chromosome 11 and functions as both a folate hydrolase and a neuropeptidase. Inhibition of brain GCPII may have therapeutic potential in the treatment of certain disease states arising from pathologically overactivated glutamate receptors. Recently, we reported that certain urea-based structures act as potent inhibitors of GCPII (J. Med. Chem. 2001, 44, 298). However, many of the potent GCPII inhibitors prepared to date are highly polar compounds and therefore do not readily penetrate the blood-brain barrier. Herein, we elaborate on the synthesis of a series of potent, urea-based GCPII inhibitors from the lead compound 3 and provide assay data for these ligands against human GCPII. Moreover, we provide data revealing the ability of one of these compounds, namely, 8d, to reduce the perception of inflammatory pain. Within the present series, the γ-tetrazole bearing glutamate isostere 7d is the most potent inhibitor with a Ki of 0.9 nM. The biological evaluation of these compounds revealed that the active site of GCPII likely comprises two regions, namely, the pharmacophore subpocket and the nonpharmacophore subpocket. The pharmacophore subpocket is very sensitive to structural changes, and thus, it appears important to keep one of the glutamic acid moieties intact to maintain the potency of the GCPII inhibitors. The site encompassing the nonpharmacophore subpocket that binds to glutamate's α-carboxyl group is sensitive to structural change, as shown by compounds 6b and 7b. However, the other region of the nonpharmacophore subpocket can accommodate both hydrophobic and hydrophilic groups. Thus, an aromatic ring can be introduced to the inhibitor, as in 8b and 8d, thereby increasing its hydrophobicity and thus potentially its ability to cross the blood-brain barrier. Intrathecally administered 8d significantly reduced pain perception in the formalin model of rat sensory nerve injury. A maximal dose of morphine (10 mg) applied in the same experimental paradigm provided no significant increase in analgesia in comparison to 8d during phase 1 of this pain study and modestly greater analgesia than 8d in phase 2. These urea-based inhibitors of GCPII thus offer a novel approach to pain management.
