Potential Anticancer Agents. V. Some Sulfur-Substituted Derivatives of Cysteine<sup>1</sup>

Goodman, Leon; Ross, Leonard O.; Baker, B. R.

doi:10.1021/jo01103a004

Cited by 37 publications

(5 citation statements)

References 2 publications

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“…The specific radioactivity of the carboxymethylcysteine was unchanged after co-chromatography with cold carrier on AG 50. In order to test for the presence of a thioether linkage, the product was oxidized with hydrogen peroxide by the procedure of Goodman et al (1958). After this treatment, which does not affect oxygen ethers, the chromatographic behavior of the product in methyl ethyl ketone-propionic acid-water was changed, consistent with its oxidation to the sulfone.…”

Section: Subunit Molecular Weight and Number Of Bindingmentioning

confidence: 99%

Reaction mechanism and structure of the active site of proline racemase

Rudnick¹,

Abeles²

1975

Biochemistry

128

100

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Proline racemase catalyzes the interconversion of D- and L-proline. Previous studies in this laboratory have established that the reaction proceeds by means of a two-base mechanism in which one base on the enzyme removes the substrate alpha-hydrogen as a proton and the conjugate acid of another base donates a proton to the opposite side of the alpha-carbon (Cardinale, G.J., and Abeles, R.H., (1968), Biochemistry 7, 3970. An assumption of the proposed mechanism was that no proton exchange occurs from the enzyme-substrate complex. In the present study, we have shown that the rate of 3H release from DL-[alpha-3H]proline, in the presence of proline racemase, decreases with increasing proline concentrations. These results establish that release of the substrate derived proton from the enzyme occurs largely, possibly exclusively, after release of the product. Under initial velocity conditions, the rate of 3H release from L-[alpha-3H]proline is not reduced with increasing L-proline concentrations. Thus, the enzyme-bound proton derived from one isomer can only be "captured" by the other isomer. We conclude that there are two forms of the enzyme; one binds L-proline and the other D-proline. Release of the substrate derived proton from enzyme is more rapid than the interconversion of these two forms. These results are consistent with the previously proposed mechanism. Proline racemase is composed of similar subunits of mol wt 38,000 as determined by gel electrophoresis in the presence of sodium dodecyl sulfate. Equilibrium dialysis experiments detect only one substrate binding site for every two subunits. When the oxidized form of the enzyme, which is inactive and cannot bind substrate, is reduced by thiol to yield active enzyme, two cysteine sulfhydryl groups per dimer become available to react with iodoacetate. Inactivation of the enzyme occurs upon modification of one of these cysteines. All iodoacetate incorporation occurs at the same point in the primary sequence of the enzyme, and can be prevented by the presence of proline or pyrrole-2-carboxylate, a substrate analog. A model is proposed in which a single active site is formed by elements of two identical subunits. Although the data are consistent with this model, another interpretation, in which half of the subunits are nonfunctional, cannot be ruled out.

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Section: Subunit Molecular Weight and Number Of Bindingmentioning

confidence: 99%

Reaction mechanism and structure of the active site of proline racemase

Rudnick¹,

Abeles²

1975

Biochemistry

128

100

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“…The most potent growth inhibition activity was exhibited by 36 (GI 50 ≈ 34 nM), which was ∼30-fold better than 37 without the α-carboxylate, highlighting the importance of achieving the correct physicochemical balance. S - Alkylated derivatives of cysteine were first designed as anticancer agents following the observation that radiolabeled cysteine was incorporated by leukemic white blood cells, , so active uptake of the amino acid zwitterion also cannot be discounted as contributing to the improved activity of 36 compared with 37 . Next, we transferred the optimal dialkyl substituent pattern to the butanamine scaffold.…”

Section: Resultsmentioning

confidence: 99%

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

et al. 2013

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The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-l-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (Kiapp < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

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“…In recent years, the development of new sustainable methodologies has gained the attention of the scientific community, leading to the application of environmentally benign synthetic procedures. [11] Organochalcogen compounds are gaining increasing interest in the area of synthesis, mainly because of their impressive potential application in the biological sciences, [12] as anticancer, [13][14][15][16] anti-Alzheimer, [17][18][19][20] antimicrobial, [21][22][23] antiviral, [24][25][26] anti-inflammatory, [27][28][29] anti-diabetic, [30][31][32] and antidepressant agents, [33][34][35] among other uses. [36][37][38] They also play a significant role in modern organic synthesis and materials science.…”

Section: Introductionmentioning

confidence: 99%

“…Organochalcogen compounds are gaining increasing interest in the area of synthesis, mainly because of their impressive potential application in the biological sciences, as anti‐cancer, anti‐Alzheimer, antimicrobial, antiviral, anti‐inflammatory, anti‐diabetic, and antidepressant agents, among other uses . They also play a significant role in modern organic synthesis and materials science .…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Electrochemical Chalcogen (S/Se)‐Functionalization of Organic Molecules

et al. 2019

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Achieving advances in the development of clean and efficient synthetic routes has become an important aim in research. In recent years, the search for new sustainable methodologies, notably environmentally benign synthetic procedures, has gained the attention of the scientific community. Electrosynthesis is a tool that has been extensively studied due to its potential application in chemical transformations and it adheres to the principles of green chemistry. Organochalogen compounds form an important class of molecules, since many of them have properties that can be applied in medicine and materials science. Thus, herein we provide a comprehensive and updated overview covering recent advances in the electrochemical C(sp2)−H bond chalcogenation of activated arenes and heterocycles as well as electrochemical chalcogenation through oxidative cross‐coupling reactions and chalcogen‐functionalization of alkenes/alkynes. The scope, limitations, and mechanisms are described and discussed, detailing the fundamental aspects and benefits of electrochemistry for the chalcogenation of organic compounds. The content of this Minireview demonstrates that it is possible to provide new synthetic routes and to improve the existing methodologies, to obtain processes more in line with current environmental protection aims. The reader will also find a discussion on the fundamental aspects and benefits of applying electrosynthesis to the assembly and operation of an electrolytic cell.

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Potential Anticancer Agents. V. Some Sulfur-Substituted Derivatives of Cysteine¹

Cited by 37 publications

References 2 publications

Reaction mechanism and structure of the active site of proline racemase

Reaction mechanism and structure of the active site of proline racemase

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

Recent Advances in Electrochemical Chalcogen (S/Se)‐Functionalization of Organic Molecules

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Potential Anticancer Agents. V. Some Sulfur-Substituted Derivatives of Cysteine1

Cited by 37 publications

References 2 publications

Reaction mechanism and structure of the active site of proline racemase

Reaction mechanism and structure of the active site of proline racemase

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

Recent Advances in Electrochemical Chalcogen (S/Se)‐Functionalization of Organic Molecules

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Potential Anticancer Agents. V. Some Sulfur-Substituted Derivatives of Cysteine¹