東華大學圖書館 |

Language: English

Help

回圖書館首頁

手機版館藏查詢

Back

Switch To: Labeled | MARC Mode | ISBD

Linked to FindBook

Google Book

Amazon

博客來

Design, Synthesis, and Application of a Rapidly Diversifiable Trioxacarcin Pharmacophore in Antibody-Drug Conjugates.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Design, Synthesis, and Application of a Rapidly Diversifiable Trioxacarcin Pharmacophore in Antibody-Drug Conjugates./
Author:	Anesini, Jason E.
Description:	1 online resource (357 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
Contained By:	Dissertations Abstracts International84-12B.
Subject:	Chemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30247036click for full text (PQDT)
ISBN:	9798379604622

Design, Synthesis, and Application of a Rapidly Diversifiable Trioxacarcin Pharmacophore in Antibody-Drug Conjugates.
Anesini, Jason E.

Design, Synthesis, and Application of a Rapidly Diversifiable Trioxacarcin Pharmacophore in Antibody-Drug Conjugates. - 1 online resource (357 pages)

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2023.

Includes bibliographical references

The trioxacarcin natural products are structurally complex, densely oxygenated bacterial isolates with exquisite biological activity towards a number of different human cancer cell lines. Following an initial isolation report in 1981, a distinct member of the trioxacarcins, LL-D49194α1, was selected for a phase 1 clinical study because of its promising pre-clinical anti-tumor activity. While a number of positive responses were observed in the cohort of 15 patients, the trial was suspended immediately following the death of a woman in the study. Retrospective analysis of the cohort indicated that systemic dosing of trioxacarcins realized non-specific pancarditis at doses that produced any meaningful reduction in tumor volume. In response to the deleterious off-target toxicity natural products like the trioxacarcins typically display, antibody-drug conjugates (ADCs) have emerged as a robust technology to selectively deliver these toxic payloads to a cancer cell. In an ADC, the small molecule warhead is linked to a monoclonal antibody which recognizes a receptor the cancer cell overexpresses relative to normal human cells. Once the entire construct enters the cancer cell, the linkage is engineered to release the payload which as the free drug can then affect cell apoptosis through its distinct mechanism of action. This dissertation presents the most recent step towards the realization of a fully-synthetic trioxacarcins as a suitable payload for an ADC. A halohydrin prodrug of the spiro-epoxide, present in all biologically active trioxacarcins, is utilized as a novel handle upon which to build the first stable trioxacarcin ADC with modest potency against human cancer cell lines. A rapidly diversifiable trioxacarcin pharmacophore is then developed and employed to understand how the linkage site of the trioxacarcin to the antibody effects the resultant properties of the ADC.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798379604622Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Antibody-drug conjugatesIndex Terms--Genre/Form:

542853
Electronic books.

Design, Synthesis, and Application of a Rapidly Diversifiable Trioxacarcin Pharmacophore in Antibody-Drug Conjugates.
LDR:03283nmm a2200385K 4500 001 2362949
005 20231109104713.5
006 m o d
007 cr mn ---uuuuu
008 241011s2023 xx obm 000 0 eng d
020 $a 9798379604622
035 $a (MiAaPQ)AAI30247036
035 $a AAI30247036
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Anesini, Jason E. $3 3703694
245 1 0 $a Design, Synthesis, and Application of a Rapidly Diversifiable Trioxacarcin Pharmacophore in Antibody-Drug Conjugates.
264 0 $c 2023
300 $a 1 online resource (357 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
500 $a Advisor: Myers, Andrew G.
502 $a Thesis (Ph.D.)--Harvard University, 2023.
504 $a Includes bibliographical references
520 $a The trioxacarcin natural products are structurally complex, densely oxygenated bacterial isolates with exquisite biological activity towards a number of different human cancer cell lines. Following an initial isolation report in 1981, a distinct member of the trioxacarcins, LL-D49194α1, was selected for a phase 1 clinical study because of its promising pre-clinical anti-tumor activity. While a number of positive responses were observed in the cohort of 15 patients, the trial was suspended immediately following the death of a woman in the study. Retrospective analysis of the cohort indicated that systemic dosing of trioxacarcins realized non-specific pancarditis at doses that produced any meaningful reduction in tumor volume. In response to the deleterious off-target toxicity natural products like the trioxacarcins typically display, antibody-drug conjugates (ADCs) have emerged as a robust technology to selectively deliver these toxic payloads to a cancer cell. In an ADC, the small molecule warhead is linked to a monoclonal antibody which recognizes a receptor the cancer cell overexpresses relative to normal human cells. Once the entire construct enters the cancer cell, the linkage is engineered to release the payload which as the free drug can then affect cell apoptosis through its distinct mechanism of action. This dissertation presents the most recent step towards the realization of a fully-synthetic trioxacarcins as a suitable payload for an ADC. A halohydrin prodrug of the spiro-epoxide, present in all biologically active trioxacarcins, is utilized as a novel handle upon which to build the first stable trioxacarcin ADC with modest potency against human cancer cell lines. A rapidly diversifiable trioxacarcin pharmacophore is then developed and employed to understand how the linkage site of the trioxacarcin to the antibody effects the resultant properties of the ADC.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Chemistry. $3 516420
650 4 $a Cellular biology. $3 3172791
650 4 $a Oncology. $3 751006
653 $a Antibody-drug conjugates
653 $a Oncology
653 $a Organic chemistry
653 $a Total synthesis
655 7 $a Electronic books. $2 lcsh $3 542853
690 $a 0485
690 $a 0379
690 $a 0992
710 2 $a ProQuest Information and Learning Co. $3 783688
710 2 $a Harvard University. $b Chemistry and Chemical Biology. $3 2094763
773 0 $t Dissertations Abstracts International $g 84-12B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30247036 $z click for full text (PQDT)