ChemInform Abstract: An Improved Synthesis of 7‐Substituted Pyrrolo[3,2‐d]pyrimidines.

Elliott, Arthur J.; Morris, Phillip; Petty, Sandra L.; Williams, Carl H.

doi:10.1002/chin.199816149

Cited by 2 publications

(2 citation statements)

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“…Acid catalyzed condensation of pyrrole 7 (Figure ) with acetonitrile afforded bicyclic 8 in 72% yield. Next, 8 was chlorinated with POCl 3 to generate 9 in 87% yield.…”

Section: Chemistrymentioning

confidence: 99%

Discovery of Antitubulin Agents with Antiangiogenic Activity as Single Entities with Multitarget Chemotherapy Potential

Gangjee

Pavana

Ihnat

et al. 2014

ACS Med. Chem. Lett.

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Antiangiogenic agents (AA) are cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2 inhibitory activity (comparable to that of sunitinib) with potent antitubulin activity (comparable to that of combretastatin A-4 (CA)) in a single molecule, with GI50 values of 10(-7) M across the entire NCI 60 tumor cell panel. It potently inhibited tubulin assembly and circumvented the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to antimicrotubule agents. The compound is freely water-soluble as its HCl salt and afforded excellent antitumor activity in vivo, superior to docetaxel, sunitinib, or Temozolomide, without any toxicity.

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“…Acid catalyzed condensation of pyrrole 7 (Figure ) with acetonitrile afforded bicyclic 8 in 72% yield. Next, 8 was chlorinated with POCl 3 to generate 9 in 87% yield.…”

Section: Chemistrymentioning

confidence: 99%

Discovery of Antitubulin Agents with Antiangiogenic Activity as Single Entities with Multitarget Chemotherapy Potential

Gangjee

Pavana

Ihnat

et al. 2014

ACS Med. Chem. Lett.

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“…An early synthetic route was developed for synthesizing first-generation inhibitors [20]; this route provided a general method for producing analogues with varying aromatic or cycloalkyl substituents in the 9-position (Scheme 18.1). The desired aromatic or alicyclic substituent was introduced by using the corresponding aldehyde as a starting material.…”

Section: Chemistry Of First-generation Pnp Inhibitorsmentioning

confidence: 99%

The Design of Forodesine HCl and Other Purine Nucleoside Phosphorylase Inhibitors

Morris

Kamath

2008

Modified Nucleosides

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Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme that catalyzes the reversible phosphorolysis of purine nucleosides such as 2 0 -deoxyguanosine (dGuo) and 2 0 -deoxyinosine to their respective bases and deoxyribose-a-1-phosphate [1][2][3][4][5]. In cells, PNP normally acts in the phosphorolytic direction, since the 6-oxopurine metabolic products are further metabolized. The importance of PNP to the integrity of the immune system became apparent with the description of a rare form of immune deficiency found in children who are genetically deficient in the PNP enzyme [6]. Children lacking the PNP enzyme have severe T-cell immunodeficiency while, in most cases, maintaining normal or high B-cell function. The biochemical mechanism underlying the T-cell selective immunosuppression in PNP-deficient patients has been extensively studied. Metabolically, these patients have a low uric acid concentration as they lack the necessary hypoxanthine or guanine substrates. These patients also have elevated levels of the nucleosides 2 0 -deoxyguanosine, 2 0 -deoxyinosine, inosine and guanosine as they lack the PNP enzyme necessary to catabolize these materials. While all nucleoside levels are elevated, only dGuo affects the T-cell population. As the concentration of dGuo increases within cells, it accumulates and is phosphorylated to 2 0 -deoxyguanosine phosphate (dGMP) by the enzyme 2 0 -deoxycytidine kinase. Subsequently, dGMP is converted to 2 0 -deoxyguanosine diphosphate (dGDP), which is then further converted to the triphosphate (dGTP) [7,8]. The elevated dGTP level creates an imbalance in the endogenous nucleotide pool, which in turn induces apoptosis (Figure 18.1).The unique sensitivity of human T cells to PNP deficiency is attributed to a relatively high level of kinase and a low level of nucleotidase activity compared to other cell types. This unique enzyme ratio is especially characteristic of immature T cells. Based upon these observations, several novel classes of PNP inhibitors have been designed for the treatment of T-cell-mediated diseases. Among the diseases Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn

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ChemInform Abstract: An Improved Synthesis of 7‐Substituted Pyrrolo[3,2‐d]pyrimidines.

Cited by 2 publications

References 1 publication

Discovery of Antitubulin Agents with Antiangiogenic Activity as Single Entities with Multitarget Chemotherapy Potential

Discovery of Antitubulin Agents with Antiangiogenic Activity as Single Entities with Multitarget Chemotherapy Potential

The Design of Forodesine HCl and Other Purine Nucleoside Phosphorylase Inhibitors

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