A new dendrimer scaffold for preparing dimers or tetramers of biologically active molecules

Raju, Natarajan; Ranganathan, Rama S.; Tweedle, M. F.; Swenson, Rolf E.

doi:10.1016/j.tetlet.2005.01.026

Cited by 10 publications

(7 citation statements)

References 15 publications

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“…The (TKPPR) 2 and (TKPPR) 4 entities are a synthetic homodimer and a homotetramer of TKPPR labeled with Oregon Green, a fluorescent dye that allows detection. These were synthesized and characterized by Raju (11). Recalling our multivalency results from the heterodimer project above allows us to understand the next results in rows 5-7.…”

Section: Multivalency In a Large Particlementioning

confidence: 94%

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Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, France

Tweedle¹

2006

Contrast Media Mol Imaging

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This review discusses multivalency in the context of drug discovery, specifically the discovery of new diagnostic imaging and related agents. The aim is to draw attention to the powerful role that multivalency plays throughout research involving molecular biology, in general, and much of biochemically targeted contrast agent research, in particular. Two examples from the author's laboratory are described. We created small ($5 kDa) peptide 'dimers' composed of two different, chemically linked peptides. The monomer peptides both bound to the same target protein with K d % 100 s nM, while the heterodimers had sub-nM K d values. Biological activity was evident in the heterodimers where none or very little existed in homodimers, monomers or monomer mixtures. Two different tyrosine kinases (KDR and C-Met) and four peptide families produced consistent results: multivalent heterodimers were uniquely different. The second example begins with making two micron ultrasound bubbles coated with the peptide, TKPPR (a Tuftsin antagonist) as a negative control for bubbles targeted with angiogenesis target-binding peptides. Unexpected binding of a 'negative' control, (TKPPR)-targeted bubble to endothelial cells expressing angiogenesis targets, led to the surprising result that TKPPR, only when multimerized, binds avidly, specifically and actively to neuropilin-1, a VEGF co-receptor. VEGF is the primary stimulator of angiogenesis. Tuftsin is a small peptide (TKPR) derived from IgG that binds to macrophages during inflammation, and has been studied for over 30 years. The receptor has never been cloned. The results led to new conclusions about Tuftsin, neuropilin-1 and the purpose, up to now unknown, of exon 8 in VEGF. Multivalency can be used rationally to solve practical problems in drug discovery. When targeting larger structures, multivalency is frequently unavoidable, and can lead to unpredictable and useful biochemical information, as well as to new drug candidates.

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Section: Multivalency In a Large Particlementioning

confidence: 94%

“…The primary references for the original work discussed in this review are references (6,7,9,11). I thank my coauthors and collaborators for their outstanding scientific work and their never ceasing support.…”

Section: Acknowledgementsmentioning

confidence: 99%

Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, France

Tweedle¹

2006

Contrast Media Mol Imaging

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“…Synthesis of TKPPR Multimers-Multimeric TKPPR constructs tagged with Oregon Green fluorescent marker were prepared using solution phase chemistry as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

Tuftsin Binds Neuropilin-1 through a Sequence Similar to That Encoded by Exon 8 of Vascular Endothelial Growth Factor

Wronski

Raju

Pillai

et al. 2006

Journal of Biological Chemistry

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112

117

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“…Compounds 3b and 3d (Table 1) were also prepared by Dieckmann condensation from the corresponding diesters. The requisite amino-diesters 2a-2h were prepared by aza-Michael reaction, using modified literature procedures (31)(32)(33)(34). Formation of 7-membered or larger rings failed, as mixtures were obtained.…”

Section: Resultsmentioning

confidence: 99%

High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide

Popović‐Djordjević

Stepanović

Došen‐Mićović

et al. 2016

Green Chemistry Letters and Reviews

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It was found that NaH suspension in DMSO was highly activated when reacted with an alcohol. The in situ generated NaH/alkoxide mixture permitted very rapid and complete deprotonation and acylation of various cyclic ketones with alkyl carbonates at ambient temperature. Activated NaH/ alkoxide in DMSO is particularly effective in Dieckmann condensations, where it affords 5-and 6membered carbocyclic or N-containing heterocyclic β-keto esters in high yields. A heterocyclic Dieckmann condensation was performed on a molar scale, demonstrating the scalability of the procedure. Besides, DMSO is non-toxic, relatively inexpensive and environmentally benign solvent.

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A new dendrimer scaffold for preparing dimers or tetramers of biologically active molecules

Cited by 10 publications

References 15 publications

Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, France

Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, France

Tuftsin Binds Neuropilin-1 through a Sequence Similar to That Encoded by Exon 8 of Vascular Endothelial Growth Factor

High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide

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