Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage

Jiang, Yongying

doi:10.1016/j.bmcl.2006.10.017

Cited by 18 publications

(3 citation statements)

References 30 publications

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“…The optimal conjugate was also efficacious in nude mice causing a 95% decrease in serum PSA levels and 87% reduction of tumor weight . Similarly, PSA‐targeted prodrugs of paclitaxel, thapsigargin, diazeniumdiolate, protoxin, 5‐fluoro‐2′‐deoxyuridine, nitrogen mustard, doxorubicin, and vinblastine were designed and evaluated in PSA‐producing prostate tumor cell lines as well as in vivo in mouse models as discussed in the following sections. Among the PSA‐activated prodrugs developed over the past two decades, the doxorubicin conjugate glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln‐Ser‐Leu‐dox (L‐377,202) was advanced to clinical trials to demonstrate proof‐of‐concept .…”

Section: Targeted Prodrug Approachesmentioning

confidence: 99%

“…Due to its ability to spontaneously decompose to phosphoramide mustard under physiological conditions, 4‐aminocyclophosphamide (4‐NH 2 ‐CPA) was used as a prodrug moiety. The feasibility of designing 4‐NH 2 ‐CPA peptide conjugates was first evaluated as model prodrugs for activation by proteases and cis ‐( 2R , 4R )‐4‐NH 2 ‐CPA found to be required stereochemically for proteolytic activation . Subsequent synthesis and evaluation of various 4‐NH 2 ‐CPA tetrapeptide conjugates 22 showed that PSA cleavage was stereoselective and that the cis ‐( 2R, 4R )‐isomer was activated by PSA with a half‐life of 12 min (Fig.…”

Section: Targeted Prodrug Approachesmentioning

confidence: 99%

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Targeted Prodrug Approaches for Hormone Refractory Prostate Cancer

Aloysius

2014

Medicinal Research Reviews

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Due to the propensity of relapse and resistance with prolonged androgen deprivation therapy (ADT), there is a growing interest in developing non-hormonal therapeutic approaches as alternative treatment modalities for hormone refractory prostate cancer (HRPC). Although the standard treatment for HRPC consists of a combination of ADT with taxanes and anthracyclines, the clinical use of chemotherapeutics is limited by systemic toxicity stemming from nondiscriminatory drug exposure to normal tissues. In order to improve the tumor selectivity of chemotherapeutics, various targeted prodrug approaches have been explored. Antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) strategies leverage tumor-specific antigens and transcription factors for the specific delivery of cytotoxic anticancer agents using various prodrug-activating enzymes. In prostate cancer, overexpression of tumor-specific proteases such as prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) is being exploited for selective activation of anticancer prodrugs designed to be activated through proteolysis by these prostate cancer-specific enzymes. PSMA- and PSA-activated prodrugs typically comprise an engineered high-specificity protease peptide substrate coupled to a potent cytotoxic agent via a linker for rapid release of cytotoxic species in the vicinity of prostate cancer cells following proteolytic cleavage. Over the past two decades, various such prodrugs have been developed and they were effective at inhibiting prostate tumor growth in rodent models; several of these prodrug approaches have been advanced to clinical trials and may be developed into effective therapies for HRPC.

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Section: Targeted Prodrug Approachesmentioning

confidence: 99%

Section: Targeted Prodrug Approachesmentioning

confidence: 99%

Targeted Prodrug Approaches for Hormone Refractory Prostate Cancer

Aloysius

2014

Medicinal Research Reviews

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“…Moreover, its enzymatic activity is restricted to the tumor microenvironment due to inactivation by α 1‐antichymotrypsin and α 2‐macroglobulin in the systemic circulation , which makes PSA an attractive target for tumor‐selective prodrug activation. Several prodrugs consisting of PSA‐specific peptide substrates coupled to cytotoxic drugs have been reported .…”

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Improving the Specificity of the Prostate‐Specific Antigen Substrate Glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln as a Promoiety

Aloysius

2015

Chem Biol Drug Des

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To develop PSA peptide substrates with improved specificity and plasma stability from the known substrate sequence glutaryl-Hyp-Ala-Ser-Chg-Gln, systematic replacements of the N-terminal segment with D-retro-inverso-peptides were performed with the incorporation of 7-amino-4-methylcoumarin (7-AMC) after Gln for convenient fluorometric determination and ranking of the PSA substrate activity. The D-retro-inverso-peptide conjugates with P2-P5 D-amino acid substitutions were moderate but poorer PSA substrates as compared to the original peptide, suggesting that inversion of the amide bonds and/or incorporation of the additional atom as in the urea linker adversely affected PSA binding. However, P5 substitution of Hyp with Ser showed significant improvements in PSA cleavage rate; the resulting AMC conjugate, glutaryl-Ser-Ala-Ser-Chg-Gln-AMC (11), exhibited the fastest PSA cleavage rate of 351 pmol/min/100 nmol PSA. In addition, GABA←mGly-Ala-Ser-Chg-Gln-AMC (conjugate 6) was the second best PSA substrate and released 7-AMC at a rate of 225 pmol/min/100 nmol PSA as compared to 171 pmol/min/100 nmol PSA for the control conjugate glutaryl-Hyp-Ala-Ser-Chg-Gln-AMC. Incubations of selected AMC conjugates with mouse and human plasma revealed that GABA←D-Ser-ψ[NH-CO-NH]-Ala-Ser-Chg-Gln-AMC (5) and GABA←mGly-Ala-Ser-Chg-Gln-AMC (6) were most stable to non-PSA-mediated proteolysis. Our results suggest that the PSA specificity of glutaryl-Hyp-Ala-Ser-Chg-Gln is improved with Ser and mGly substitutions of Hyp at the P5.

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Phosphoramides: Synthesis, Spectroscopy, and X‐ray Crystallography

Gholivand

Shariatinia‬

Oroujzadeh

2013

Heteroatom Chemistry

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A series of new phosphoramides with general formula RP(O)X 2 , where R = amino/pmethylphenoxy and X = amine, were synthesized and characterized by 1 H, 13 C, 31 P nuclear magnetic resonance (NMR), and infrared (IR) spectroscopy and elemental analysis. The 31 P{ 1 H}NMR spectra show that among compounds 7-9 containing 2-, 3-, and 4-aminopyridinyl moieties, respectively, the shielding order of the P atom decreases as 7 > 9 > 8.

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Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage

Cited by 18 publications

References 30 publications

Targeted Prodrug Approaches for Hormone Refractory Prostate Cancer

Targeted Prodrug Approaches for Hormone Refractory Prostate Cancer

Improving the Specificity of the Prostate‐Specific Antigen Substrate Glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln as a Promoiety

Phosphoramides: Synthesis, Spectroscopy, and X‐ray Crystallography

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