Cyclization-activated prodrugs. Basic carbamates of 4-hydroxyanisole

Saari, W. S.; Schwering, John E.; Lyle, Paulette A.; Smith, Steven J.; Engelhardt, Edward L.

doi:10.1021/jm00163a016

Cited by 108 publications

(83 citation statements)

References 6 publications

(8 reference statements)

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“…A classical example is that of aminocarbamate prodrugs 9 of 4-hydroxyanisole, prepared by Saari et al, who found them to release the parent compound by intramolecular cyclization of the carrier moieties to imidazolidin-2-ones 10 (Scheme 7) and not to be susceptible to murine plasma esterases [25]. All the compounds tested were stable at low pH but were reactive in neutral and alkaline medium, releasing 4-hydroxyanisole at rates that were structure dependent (t 1/2 ranging from 36 to 942 min, at pH 7.4 and 37 ºC).…”

Section: General Basic Amine Carriersmentioning

confidence: 99%

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Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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Section: General Basic Amine Carriersmentioning

confidence: 99%

“…This implies that, for n>3, intramolecular activation is unlikely to increase reaction rates. In what concerns the introduction of Nmethyl (R 1 , R 2 , R 3 ) or N-ethyl substituents (R 1 , R 2 ), di-and tri-methyl derivatives were more reactive than their unsubstituted, mono-methyl and di-ethyl counterparts [25]. Scheme 7.…”

Section: General Basic Amine Carriersmentioning

confidence: 99%

Cyclization-activated Prodrugs

2007

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“…N-Boc-aminopropoxy quinolinecarboxamide 5 was carried out the O-alkylation of quinolinecarboxamide 3 with N-Boc-3-bromopropoxyamine using K 2 CO 3 in refluxing acetonitrile, 15 followed by the treatment with 2 M HCl etherate 16 generating aminopropoxy quinolinecarboxamide salt 6 in 93 % overall yield. It should be noted that the solubility of quinolinecarboxamide 3 was transformated from organic solubility to the enhanced aqueous solubility for the pharmacological assay.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Novel Quinolinecarboxamide Derivatives with Estrogenic Activity

2003

Bulletin of the Korean Chemical Society

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Even though estrogens have a well-established role in the growth of hormone-dependant tumors by the estrogen receptor (ER)-dependant mitogenic effect in cells containing ER, 1 a member of the nuclear receptor superfamily, 2 they exert numbers of favorable activities in women. From a therapeutical point of view, estrogen and its derivatives are well known not only as oral contraceptives, but also as a major component in hormone replacement therapy (HRT) required for bone loss prevention and for the control of cardiovascular diseases in postmenopausal women. 3The most widely used estrogens are 17β-estradiol 4 and ethynylestradiol, 5 a synthetic steroidal compound. These estrogen agonists have been used for postmenopausal women required for HRT. However, it has been known that long-term usage of estrogen causes high incidence of breast cancer, 6 which leads to development of antiestrogen such as tamoxifen, the first selective ER modulator (SERM). Recently, raloxifene as a second SERM was developed to alleviate menopausal symptoms without risk of breast cancer.8 Afterwards, the more effective SERMs are being developed and tested that act as antiestrogens on breast and endometrium while having estrogenic effects on bones, the lipid profile and the central nervous system. [9][10][11] In this point of view to develop antiestrogens, we used virtual screening system based on the structure of ER. From the initial screening, we identified compound 4 that has nonsteroidal quinoline structure. More compounds were synthesized from the leader compound 4 and tested for estrogenic activity using ERα and ERβ. Results and DiscussionSynthesis of quinolinecarboxamide derivatives. Application of such multi-component condensation approach based Doebner reation 12 for the synthesis of a clinically useful * Co-corresponding authors. Hong-Sig Sin

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“…This sequence of reactions within the trigger portion of the molecule generates, on decarboxylation, a free amine in the spacer element that undergoes a spontaneous 1, 5 cyclization to release free drug and N,N-dimethyl urea. The N,NЈ-dimethyl-substituted ethylenediamine spacer was chosen because it provides for a more rapid cyclization reaction than the unsubstituted spacer (20).…”

Section: Resultsmentioning

confidence: 99%

In vivo activity in a catalytic antibody-prodrug system: Antibody catalyzed etoposide prodrug activation for selective chemotherapy

Shabat

Lode

Pertl

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Effective chemotherapy remains a key issue for successful cancer treatment in general and neuroblastoma in particular. Here we report a chemotherapeutic strategy based on catalytic antibodymediated prodrug activation. To study this approach in an animal model of neuroblastoma, we have synthesized prodrugs of etoposide, a drug widely used to treat this cancer in humans. The prodrug incorporates a trigger portion designed to be released by sequential retro-aldol͞retro-Michael reactions catalyzed by aldolase antibody 38C2. This unique prodrug was greater than 10 2 -fold less toxic than etoposide itself in in vitro assays against the NXS2 neuroblastoma cell line. Drug activity was restored after activation by antibody 38C2. Proof of principle for local antibody-catalyzed prodrug activation in vivo was established in a syngeneic model of murine neuroblastoma. Mice with established 100-mm 3 s.c. tumors who received one intratumoral injection of antibody 38C2 followed by systemic i.p. injections with the etoposide prodrug showed a 75% reduction in s.c. tumor growth. In contrast, injection of either antibody or prodrug alone had no antitumor effect. Systemic injections of etoposide at the maximum tolerated dose were significantly less effective than the intratumoral antibody 38C2 and systemic etoposide prodrug combination. Significantly, mice treated with the prodrug at 30-fold the maximum tolerated dose of etoposide showed no signs of prodrug toxicity, indicating that the prodrug is not activated by endogenous enzymes. These results suggest that this strategy may provide a new and potentially nonimmunogenic approach for targeted cancer chemotherapy.

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Cyclization-activated prodrugs. Basic carbamates of 4-hydroxyanisole

Cited by 108 publications

References 6 publications

Cyclization-activated Prodrugs

Cyclization-activated Prodrugs

Synthesis of Novel Quinolinecarboxamide Derivatives with Estrogenic Activity

In vivo activity in a catalytic antibody-prodrug system: Antibody catalyzed etoposide prodrug activation for selective chemotherapy

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