Delving into the Latest Updates on Amonafide Maleate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Amonafide L-Malate(USAN)

+ [5]

Target

DNA x Top II

Mechanism

DNA inhibitors(DNA inhibitors), Top II inhibitors(Topoisomerase II inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesUrogenital Diseases

Active Indication-

Inactive Indication

Acute Myeloid LeukemiaAdult Acute Myeloblastic LeukemiaCastration-Resistant Prostatic Cancer

Originator Organization

Antisoma, Inc.

Active Organization-

Inactive Organization

Antisoma Research Ltd.

Antisoma, Inc.

Drug Highest PhasePendingPhase 3

First Approval Date-

Regulation-

Structure

Molecular FormulaC20H23N3O7

InChIKeyJNZBHHQBPHSOMU-WNQIDUERSA-N

CAS Registry618863-54-0

Leveraging the elevated hydrogen peroxide (H₂O₂) levels in cancer cells, H₂O₂-activated prodrugs have emerged as promising candidates for anticancer therapy. Notably, the efficacy of these prodrugs is influenced by the varying H₂O₂ levels across different cancer cell types. In this context, we have developed a novel H₂O₂-activated prodrug, PBE-AMF, which incorporates a phenylboronic ester (PBE) motif. Upon H₂O₂ exposure, PBE-AMF liberates the fluorescent and cytotoxic molecule amonafide (AMF), functioning as a theranostic agent. Our studies with PBE-AMF have demonstrated a positive correlation between intracellular H₂O₂ concentration and anticancer activity. The breast cancer cell line MDA-MB-231, characterized by high H₂O₂ content, showed the greatest susceptibility to this prodrug. Subsequently, we replaced the PBE structure with phenylboronic acid (PBA) to obtain the prodrug PBA-AMF, which exhibited enhanced stability, aqueous solubility, and tumor cell selectivity. This selectivity is attributed to its affinity for sialic acid, which is overexpressed on the surfaces of cancer cells. In vitro assays confirmed that PBA-AMF potently and selectively inhibited the proliferation of MDA-MB-231 cells, while sparing non-cancerous MCF-10A cells. Mechanistic investigations indicated that PBA-AMF impedes tumor proliferation by inhibiting DNA synthesis, reducing ATP levels, inducing apoptosis, and arresting the cell cycle. Our work broadens the range of small molecule H₂O₂-activated anticancer theranostic prodrugs, which are currently limited in number. We anticipate that the applications of PBA-AMF will extend to a wider spectrum of tumors and other diseases associated with increased H₂O₂ levels, thereby offering new horizons in cancer diagnostics and treatment.

01 Mar 2024·Bioorganic Chemistry

Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode

Article

Author: Gao, Yun-Fei ; Xia, Ya-Mu ; Sun, Ping ; Zhang, Xue ; Zhang, Jia-Yin ; Gao, Wei-Wei ; Liang, Chen ; Yu, Ri-Lei ; Xu, Na ; Zhang, Qi-Ming

In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-11) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-12) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 (D-12) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods. Electrochemical biosensors were obtained through the immobilization of ctDNA, G-quadruplexes, poly(dG), and poly(dA), respectively, on the clean surface of GCE. After the incubation of biosensors with D-11 or D-12, the peaks of dGuo and dAdo decreased prominently, and the peak of 8-oxoGua appeared at +0.50 V, suggesting that the interaction between D-11 (D-12) and DNA could result in the oxidative damage of guanine. Unexpected, the as-prepared DNA biosensor possessed satisfactory anti-interference property and good practicability in real samples. UV-vis and fluorescence spectra, and gel electrophoresis assays were employed to further confirm the intercalation mode of D-11 (D-12) towards DNA base pairs. Moreover, D-11 was proved to exhibit stronger anti-proliferation activity than mitionafide and amonafide against both A549 and HeLa cell lines.

01 Jan 2024·Anti-Cancer Agents in Medicinal Chemistry

An Outlook of the Structure Activity Relationship (SAR) of Naphthalimide Derivatives as Anticancer Agents

Article

Author: Bhat, Aeyaz Ahmad

Abstract:The efficacy of drugs against cancer in clinical settings may be limited due to pharmacokinetic issues, side effects and the emergence of drug resistance. However, a class of anticancer drugs known as naphthalimides have proven to be very effective. These derivatives have demonstrated to be effective in treating different types of cancers and exhibit strong DNA binding affinity. The anticancer properties of the naphthalimide derivatives allow them to target a number of cancer cell lines. Researchers have investigated the anticancer activity of numerous naphthalimide derivatives, such as heterocyclic fused, non-fused substituted, metal-substituted and carboxamide derivatives. Surprisingly, some derivatives demonstrate greater activity than the reference norms, such as cisplatin, amonafide, mitonafide and others and are selective against many cell lines. The primary objective of this research is to comprehend the effects of various substitution patterns on the structure-activity relationship (SAR) of these derivatives and the instances in which they enhance or reduce this biological activity.

100 Deals associated with Amonafide Maleate

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Amonafide Maleate	-	DB05022

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 3	EE	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	UA	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	RO	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	GB	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	CA	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	TW	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	IT	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	CZ	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	RU	Antisoma Research Ltd.	01 Jun 2007
Acute Myeloid Leukemia	Phase 3	AT	Antisoma Research Ltd.	01 Jun 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00715637 (Pubmed \| J Urol) Manual	Phase 3	Acute Myeloid Leukemia First line	433	cytarabine+amonafide	(aqsaovbrfk) = bwsqacspkd ygthtyfloi (uqgemssyom ) View more	Negative	10 Apr 2015
NCT00715637 (Pubmed \| J Urol) Manual	Phase 3	Acute Myeloid Leukemia First line	433	daunorubicin+cytarabine	(aqsaovbrfk) = onxxfknnbq ygthtyfloi (uqgemssyom ) View more	Negative	10 Apr 2015
ACCEDE (ASCO2011)	Phase 3	Relapsing acute myeloid leukemia	433	AS1413 plus cytarabineAS1413 plus cytarabine	jswqkyecwe(uukcxtzbml) = vsqeyomevz nnaktujtpp (swnrqvozzn )	Negative	20 May 2011
ACCEDE (ASCO2011)	Phase 3	Relapsing acute myeloid leukemia	433	Daunorubicin plus cytarabine	jswqkyecwe(uukcxtzbml) = oywyizhgaf nnaktujtpp (swnrqvozzn )	Negative	20 May 2011
ASCO2010	Not Applicable	Acute Myeloid Leukemia \| Treatment related acute myeloid leukaemia	88	amonafide (tAML)	(exzzcpfzny) = pdkbpylrjv mjlyjaygpf (xxsdauwsuo ) View more	-	20 May 2010
ASCO2010	Not Applicable		88	amonafide (MDS→AML)	(exzzcpfzny) = tgrotmpwan mjlyjaygpf (xxsdauwsuo ) View more	-	20 May 2010
ASCO2008	Phase 2	Acute Myeloid Leukemia	88	Amonafide 600 mg/m2 + ara-C 200 mg/m2	(mrzciphfdv) = fnauonwady hmqdllmdqw (vlyfrwjlyd ) View more	-	20 May 2008
ASCO2007	Phase 2	Acute Myeloid Leukemia	80	Amonafide 600 mg/m2/day + CIV ara-C 200 mg/m2/day	(qfhaytydni) = dlfpqipwls dvlchxxcna (ysmpvvfapt ) View more	-	20 Jun 2007
ASCO2006	Phase 1	Acute Myeloid Leukemia	20	Amonafide	tktcxxtxrx(ltohkzryzp) = bspgcbruim ppzvlfwmvu (lyzvdtnjbz ) View more	-	20 Jun 2006
ASCO2005	Phase 1	Acute Myeloid Leukemia	26	Amonafide + Cytosine Arabinoside (AraC)	(whfddwljxv) = hcgpovzcuj osjdckceid (jjrshuntlb ) View more	-	01 Jun 2005