1. Introduction

Oceans cover about 70% of the earth’s surface and 95% of the biosphere. Water was the cradle of the earliest living organisms, containing approximately 75% of all living organisms. The marine environment offers a rich source of natural products with potential therapeutic applications. More than 1 million marine invertebrates and more than 25,000 species of fish have been discovered, and some of these have been shown to contain natural products with potential biological activity ^[1][2]. In recent years, marine microorganisms, have also been regarded as a valuable source of bioactive compounds, with the advantages of easy cultivation and good compound extraction repeatability ^[3]. More than 10,000 bioactive molecules that have been isolated from marine organisms, and several have been found to possess anticancer activity ^[4]. Most of these natural products with anticancer activity originate from microorganisms (bacteria, fungi, protozoa, viruses, and chromista), plantae (flowering plants like mangroves and macroalgae), and animalia (invertebrates such as sponges, tunicates, and vertebrates such as fish and whale), etc.

Oceans cover about 70% of the earth’s surface and 95% of the biosphere. Water was the cradle of the earliest living organisms, containing approximately 75% of all living organisms. The marine environment offers a rich source of natural products with potential therapeutic applications. More than 1 million marine invertebrates and more than 25,000 species of fish have been discovered, and some of these have been shown to contain natural products with potential biological activity [1,2]. In recent years, marine microorganisms, have also been regarded as a valuable source of bioactive compounds, with the advantages of easy cultivation and good compound extraction repeatability [3]. More than 10,000 bioactive molecules that have been isolated from marine organisms, and several have been found to possess anticancer activity [4]. Most of these natural products with anticancer activity originate from microorganisms (bacteria, fungi, protozoa, viruses, and chromista), plantae (flowering plants like mangroves and macroalgae), and animalia (invertebrates such as sponges, tunicates, and vertebrates such as fish and whale), etc.

Cancer is one of the leading causes of death in the world. An estimated 9.6 million people died of cancer in 2018 ^[5]. Almost 1 in 6 people die of cancer globally. With the application of new theories, modern technologies, and new drugs in basic tumor research and clinical treatment, the rising trend in tumor death in many countries has been effectively controlled ^[5]. Chemotherapy is part of the major categories of medical oncology. Despite these successes, chemotherapy’s lingering toxic side-effects are still a primary cause of morbidity and mortality in cancer survivors ^[6]. As for traditional chemotherapy drugs, most of these inhibit tumor cell proliferation by acting on the DNA synthesis and the replication of tumor cells, which have been shown to be effective but at the price of high toxicity due to a lack of selectivity. Nowadays, there are novel molecular methods for treatment using cancer drugs, including target therapy by cell surface receptors, immune-directed therapy, therapeutic vaccines, and antibody–drug conjugates (ADCs) ^[7][8]. According to the 2020 ASCO’s Annual Report, a large number of innovative drugs, which can be categorized into targeted drugs and immune drugs, have entered trials and clinical trials ^[9]. Targeted medicine can restrain tumor cell growth by blocking the signal transduction, but the recurrence rate is extremely high ^[10]. Antibody–drug conjugates have the potential for increased tumor penetration and drug resistance. It has been demonstrated that a knottin peptide–drug conjugate (KDC) can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins ^[11]. In recent years, major pharmaceutical companies and research centers have focused on monoclonal antibody drugs and bi-specific antibody drugs in targeted therapy, as well as CAR-T and immunoassay point inhibitors in immunotherapy ^[12][13][14]. Immunotherapy achieves anti-tumor therapy by stimulating the body’s immune system. In immunotherapy, mainly immune cell therapy, immune checkpoint inhibitors, tumor vaccines, and immune system regulators, the immune system is used to recognize and regulate the body’s attack on abnormal cell functions ^[14]. Small peptides, such as the thymic peptide, with their unique advantages in immunotherapy, are also very prominent. The thymic peptide used has been a non-specific adjuvant therapy for various tumors, as it can induce T cell differentiation and development, promoting its proliferation and improving T cell response to the antigen at the same time ^[15]. This kind of drug enhances the patient’s immunity, with fewer side effects.

Cancer is one of the leading causes of death in the world. An estimated 9.6 million people died of cancer in 2018 [5]. Almost 1 in 6 people die of cancer globally. With the application of new theories, modern technologies, and new drugs in basic tumor research and clinical treatment, the rising trend in tumor death in many countries has been effectively controlled [5]. Chemotherapy is part of the major categories of medical oncology. Despite these successes, chemotherapy’s lingering toxic side-effects are still a primary cause of morbidity and mortality in cancer survivors [6]. As for traditional chemotherapy drugs, most of these inhibit tumor cell proliferation by acting on the DNA synthesis and the replication of tumor cells, which have been shown to be effective but at the price of high toxicity due to a lack of selectivity. Nowadays, there are novel molecular methods for treatment using cancer drugs, including target therapy by cell surface receptors, immune-directed therapy, therapeutic vaccines, and antibody–drug conjugates (ADCs) [7,8]. According to the 2020 ASCO’s Annual Report, a large number of innovative drugs, which can be categorized into targeted drugs and immune drugs, have entered trials and clinical trials [9]. Targeted medicine can restrain tumor cell growth by blocking the signal transduction, but the recurrence rate is extremely high [10]. Antibody–drug conjugates have the potential for increased tumor penetration and drug resistance. It has been demonstrated that a knottin peptide–drug conjugate (KDC) can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins [11]. In recent years, major pharmaceutical companies and research centers have focused on monoclonal antibody drugs and bi-specific antibody drugs in targeted therapy, as well as CAR-T and immunoassay point inhibitors in immunotherapy [12,13,14]. Immunotherapy achieves anti-tumor therapy by stimulating the body’s immune system. In immunotherapy, mainly immune cell therapy, immune checkpoint inhibitors, tumor vaccines, and immune system regulators, the immune system is used to recognize and regulate the body’s attack on abnormal cell functions [14]. Small peptides, such as the thymic peptide, with their unique advantages in immunotherapy, are also very prominent. The thymic peptide used has been a non-specific adjuvant therapy for various tumors, as it can induce T cell differentiation and development, promoting its proliferation and improving T cell response to the antigen at the same time [15]. This kind of drug enhances the patient’s immunity, with fewer side effects.

The resistance adaptation ability of small peptides in many drug treatments and their fewer toxic side effects indicate their potential application in further developing novel drugs. Due to these medicines’ unique metabolic processes, many new study areas on the pharmaceutical aspects of protein and peptide drugs have recently emerged ^[16][17]. Many natural and synthetic peptides were characterized in recent decades, and public databases were established, such as APD3 (database of antimicrobial peptides), the Defensins Knowledgebase, the antiviral AVPdb (database of antiviral peptides), the antiparasitic ParaPep, and the CancerPPD (database of anticancer peptides and proteins) ^{[18][19][20][21][22]}. Bioactive small peptides are composed of 2–10 amino acids linked by peptide bonds. Studies have found that amino acids such as Trp, Tyr, Met, Gly, Cys, His, and Pro in the peptide chain can significantly improve the bioactivity ^[23][24]. In other words, compared with traditional chemotherapy drugs, small peptides have several advantages, such as high absorption, small size, well-defined signaling targets, and minimal toxicity. As such, they offer a new promising area of research. Besides, small peptides are just connected by a few peptide linkages, and their small molecular weight makes them easy to be modified and synthesized. Additionally, small peptides can be used as vectors to deliver drugs specifically to every cell and tissue ^[25]. However, small peptides have some disadvantages, including a short half-life, easy degradation in vivo, poor stability, etc. Many researchers have tried to modify or develop corresponding pseudo-peptide drugs or have combined small peptides with traditional therapy for tumor combination therapy to achieve better results than with a single treatment. The application of several cyclic peptides as noncovalent nuclear targeting molecular transporters of Dox has been reported ^[26]. Additionally, another work designed new peptides based on the molecular dynamics simulation (MDs) of the matuzumab-EGFR complex in a water environment. These peptides had a higher affinity to the EGFR relative to that previously reported ^[27]. The peptide modification of anticancer drugs could enhance their activity and selectivity, perhaps even circumventing multi-drug resistance ^[28].

The resistance adaptation ability of small peptides in many drug treatments and their fewer toxic side effects indicate their potential application in further developing novel drugs. Due to these medicines’ unique metabolic processes, many new study areas on the pharmaceutical aspects of protein and peptide drugs have recently emerged [16,17]. Many natural and synthetic peptides were characterized in recent decades, and public databases were established, such as APD3 (database of antimicrobial peptides), the Defensins Knowledgebase, the antiviral AVPdb (database of antiviral peptides), the antiparasitic ParaPep, and the CancerPPD (database of anticancer peptides and proteins) [18,19,20,21,22]. Bioactive small peptides are composed of 2–10 amino acids linked by peptide bonds. Studies have found that amino acids such as Trp, Tyr, Met, Gly, Cys, His, and Pro in the peptide chain can significantly improve the bioactivity [23,24]. In other words, compared with traditional chemotherapy drugs, small peptides have several advantages, such as high absorption, small size, well-defined signaling targets, and minimal toxicity. As such, they offer a new promising area of research. Besides, small peptides are just connected by a few peptide linkages, and their small molecular weight makes them easy to be modified and synthesized. Additionally, small peptides can be used as vectors to deliver drugs specifically to every cell and tissue [25]. However, small peptides have some disadvantages, including a short half-life, easy degradation in vivo, poor stability, etc. Many researchers have tried to modify or develop corresponding pseudo-peptide drugs or have combined small peptides with traditional therapy for tumor combination therapy to achieve better results than with a single treatment. The application of several cyclic peptides as noncovalent nuclear targeting molecular transporters of Dox has been reported [26]. Additionally, another work designed new peptides based on the molecular dynamics simulation (MDs) of the matuzumab-EGFR complex in a water environment. These peptides had a higher affinity to the EGFR relative to that previously reported [27]. The peptide modification of anticancer drugs could enhance their activity and selectivity, perhaps even circumventing multi-drug resistance [28].

The marine environment is a crucial biological kingdom with the richest source of novel functional proteins and peptides. Additionally, it is gradually becoming a vital field of drug development ^[29]. As marine organisms live in a special environment that is hypersaline, high-pressure, hypoxia, and hypothermic, and lacks sunlight, these proteins and peptides have strong bioactivities and a specific structure. There are many effects associated with marine peptides, such as antioxidant, antimicrobial, antitumor, antiviral, cardioprotective, immunomodulatory, and tissue regeneration properties ^{[16][30][31][32]}. Approximately 49 marine-derived active substances or their derivatives have been approved for the market or entered clinical trials globally ^[33]. Most of these bioactive molecules are extracted from marine sponges, mollusca, and algae. There are 11 kinds of marine drugs approved by European and American drug authorities, of which, four are listed as anticancer drugs: Cytosar-U, Yondelis, Halaven, and Adcetris. In recent years, more and more studies on marine bioactive peptides have appeared. Many bioactive peptides with anticancer potential have been extracted from various marine organisms. Small peptides from marine sources are gradually gaining attention because of their uniqueness. Compared with high-molecular-weight peptides, low-molecular-weight peptides show greater molecular mobility and diffusivity, contributing to their enhanced interaction with cancer cell components and increasing their anticancer activity ^[34]. Nowadays, several newly discovered anticancer small peptides and their derivatives thereof from marine organisms have been widely applied to clinical research ^[35][36][37] (

The marine environment is a crucial biological kingdom with the richest source of novel functional proteins and peptides. Additionally, it is gradually becoming a vital field of drug development [29]. As marine organisms live in a special environment that is hypersaline, high-pressure, hypoxia, and hypothermic, and lacks sunlight, these proteins and peptides have strong bioactivities and a specific structure. There are many effects associated with marine peptides, such as antioxidant, antimicrobial, antitumor, antiviral, cardioprotective, immunomodulatory, and tissue regeneration properties [16,30,31,32]. Approximately 49 marine-derived active substances or their derivatives have been approved for the market or entered clinical trials globally [33]. Most of these bioactive molecules are extracted from marine sponges, mollusca, and algae. There are 11 kinds of marine drugs approved by European and American drug authorities, of which, four are listed as anticancer drugs: Cytosar-U, Yondelis, Halaven, and Adcetris. In recent years, more and more studies on marine bioactive peptides have appeared. Many bioactive peptides with anticancer potential have been extracted from various marine organisms. Small peptides from marine sources are gradually gaining attention because of their uniqueness. Compared with high-molecular-weight peptides, low-molecular-weight peptides show greater molecular mobility and diffusivity, contributing to their enhanced interaction with cancer cell components and increasing their anticancer activity [34]. Nowadays, several newly discovered anticancer small peptides and their derivatives thereof from marine organisms have been widely applied to clinical research [35,36,37] (

Figure 1

). Marine small peptides are molecules that participates in all processes of life activities. They can bear anticancer roles in diversiform aspects in different ways, such as preventing cell migration, induction of apoptosis, disorganization of tubulin structure and inducing cell cycle arrest, and more (

Figure 2

) [38].

Figure 1.

Figure 2.

2. Linear Peptides and Derivatives

Table 1

₅₀

Table 1

Sarcophyton glaucum

₅₀

Figure 3

Streptomyces

₅₀ value of 30.9 µM ^[60]. Tasiamide (

Table 1

Figure 3

Symploca

₅₀ values of 0.48 and 3.47 μg/mL, respectively ^[61]. Cathepsin D (Cath D) has been considered a potential target to treat cancer ^[72]. Tasiamide’s C-terminal modified derivatives have inhibitory activity against Cath D/Cath E/BACE1, potentially making them highly potent and selective Cath D inhibitors ^[62]. Belamide A (

Table 1

Figure 3

₅₀: 0.74 μM). At a concentration of 20 μM, it destroyed the micro-tubule network in rat aortic smooth muscle A-10 cells and showed the classic tubulin destabilizing mitotic characteristics ^[63]. Symplostatin 

A

Table 1

Figure 3

10

Symploca hydnoides, can cause a loss of interphase micro-tubules, G2/M arrest, and active caspase 3 and initiate the phosphorylation of Bcl-2 ^[64]. Proximicins A, B, and C (

Table 1

Figure 3

Verrucosispora

₅₀ values of 12.7 and 11.4 μg/mL, respectively ^[65]. Bisebromoamide (

Table 1

Figure 3

Lyngbya

₅₀) value across all of the cell lines (a panel of 39 human cancer cell lines (termed JFCR39)) ^[66]. Additionally, it can also inhibit the Raf/MEK/ERK and PI3K/Akt/mTOR pathways, showing a potent protein kinase inhibitor effect ^[67].

2.3. Other Small Peptides

Currently, the number of small linear anti-cancer peptides derived from marine plants is relatively small. The peptide, HVLSRAPR (

Table 1

₅₀ value of 99.88 μg/mL, while it had little inhibitory activity on LO2 cells (normal liver cells) (5.37% at 500 μg/mL). It was also shown to be selectively active on cancer cells, including Hep G2 (human liver cancer cells), MCF-7 (human breast cancer cells), SGC-7901 (human gastric cancer cells), and A549 cells ^[68].Most of the small peptides are still in the stage of structural optimization and in vitro activity verification. The lack of progress in subsequent research on their mechanisms prevents them from entering clinical development. Additionally, these small peptides merit further investigation as a potential therapeutic agent.

3. Cyclic Peptides and Derivatives

Cyclic peptides combine several favorable properties, such as a good binding affinity, target selectivity, and low toxicity, which make them attractive in anticancer drug researches ^[73]. Besides, most of the small peptides are concentrated in marine animals, and they are found to be secondary metabolites from sponges, sea squirts, cnidaria, and mollusks.

3.1. Animals

3.1.1. Metabolites of Ascidians

A significant number of compounds with unusual structures and bioactivities have been isolated from various ascidians. The cyclic hexapeptides, Mollamides B and C (

Table 2

 and 

Figure 4

), were isolated from an Indonesian tunicate 

Didemnum mole

 in 1994, along with the known peptide, Keenamide A (

Table 2

 and 

Figure 4

) [74]. Keenamide A and Mollamides B show antiproliferation activity against several cancer cell lines [74]. Keenamide A show cytotoxicity against a range of cell lines, with IC

₅₀

 values of 2.5 μg/mL toward P388, A549 and MEL-20, and 5.0 μg/mL against HT-29 cells [75]. Mollamides B inhibited the proliferation of H460 (human non-small cell lung cancer cells) and MCF-7 and SF-268 cells, but the GI

₅₀

 values are all greater than 100 μM [74]. Subsequently, the cyclic depsipeptides Trunkamide A (

Table 2

 and 

Figure 4

) was isolated from the colonial ascidian 

Lissoclinum

 sp., which was collected by Bowden and co-workers in 1996, and its structure was similar to Didemnin B. It has been found to have a cytotoxic effect on several human cancer cell lines, such as HeLa, AGS (human gastric cancer adenocytes cells), and DLD-1 (human colonic adenocarcinoma cells) cells [76]. Tamandarins A and B (

Table 2

 and 

Figure 4

), were isolated from the unidentified species of didemnid ascidian in 2000 and determined to be cyclic depsipeptides closely related to Didemnins. They were found to possess a very similar structure and biological activity to that of the Didemnin B. They were evaluated against various human cancer cell lines and slightly more potent than Didemnin B [77]. Cycloxazoline (

Table 2

 and 

Figure 4

) is an asymmetrical cyclic hexapeptide isolated from species of didemnid ascidians in 1992. It can delay S-phase cells entering the G2/M phase and induce apoptosis in HL-60 human leukemia cells [78]. These peptides are structurally similar to Didemnin B, but it’s unclear whether they have a better effect or mechanism on tumor cells.

Figure 4.

 The structures of marine bioactive cyclic peptides from Ascidians and Sponges.

Table 2.

 Marine bioactive cyclic peptides from Ascidians and Sponges.

Compound	Source	Mechanism	Cell Lines	IC50/(GI50) b	Reference
Mollamide B	Tunicate Didemnum	Cytotoxicity a	H460;	(>100 µM)	[74]
			MCF-7;
			SF-268
Mixirin C Mixirin C	HCT-116 HCT-116	1.26 µM; 1.26 µM;	Keenamide A	Tunicate Didemnum.
Mechercharmycin A Mechercharmycin A	Thermoactinomyces sp. YM3-251 Thermoactinomyces sp. YM3-251	Cytotoxicity a			P-388;	Cytotoxicity a Cytotoxicity a	2.5 µg/mL;		A549; A549;	[75]	RDTQ	5.6 mmol/L
					A-549;		2.5 µg/mL;		Virenamides A;		The Didemnid ascidian Diplosoma virens	Inhibiting the Topoisomerase II	P388;	2.5 µg/mL	[42]
MEL-20;	2.5 µg/mL;A549;		10 µg/mL
HT-29	5.0 µg/mL	HT-29;	10 µg/mL
Trunkamide A	Didemnid ascidians	Cytotoxicity a	DU-145;	7.08 nM;	[76]	CV1	10 µg/mL
			IGROV;	7.31 nM;		Virenamides B	The Didemnid ascidian Diplosoma virens	Inhibiting the Topoisomerase II	P388;
			SK-BR-3;	5 µg/mL
			5.44 nM;	A549;					5 µg/mL
HT-29;	5 µg/mL
CV1	5 µg/mL
Hela	3.90 nM
Tamandarin A	Didemnid ascidians	Cytotoxicity a	NCI-60	1.4 µM (2.3 µM)	[77]	Virenamides C	The Didemnid ascidian Diplosoma virens	Inhibiting the Topoisomerase II
Tamandarin B			P388;	5 µg/mL
A549;	5 µg/mL
HT-29;	5 µg/mL
CV1	5 µg/mL
SCAP1; (Leu-Ala-Asn-Ala-Lys)	Oyster (Saccostrea cucullata)	Enhancing oxidative DNA damage; Inducing apoptosis	HT-29	90.31 mg/mL (24 h);	[43][44][43,44]
				70.87 mg/mL (48 h);
				60.21 mg/mL (72 h)
YALPAH	Half-fin anchovy (Setipinna taty)	Inducing apoptosis	PC‑3	8.1 mg/mL	[45][46][45,46]
BCP-A (Trp-Pro-Pro)	Blood clam (Tegillarca granosa) muscle	Inducing apoptosis and inhibiting lipid peroxidation	PC-3;	1.99 mg/mL;	[47]
			DU-145;	2.80 mg/mL;
			H-1299;	3.3 mg/mL;

3.2. Fungi

Zygosporamide (

Table 3

Figure 5

Zygosporium masonii.

₅₀

₅₀

₅₀

Table 3

Figure 5

Acremonium persicinum

₅₀

Table 3

Figure 5

Figure 5.

 The structures of marine bioactive cyclic peptides from Fungi.

Table 1

Figure 3

Diplosoma virens

₅₀

₅₀

Table 1

₅₀ values of 90.31 to 60.21 μg/mL ^[43][44].

Figure 3. The structures of bioactive marine linear peptides and derivatives with anticancer potential.

With the deepening of understanding, researchers have discovered that a variety of marine small peptides can induce tumor cell apoptosis to exert anti-tumor effects. The peptide sequence was identified as YALPAH (

Table 1

Setipinna taty

₅₀

Table 1

Tegillarca granosa

₅₀

Table 1), had been successfully identified as a new inhibitor of the KV3.4 channel subunits. In particular, it had been reported that KV3.4 channels play a crucial role in cancer cell migration ^[69]. BDS-I blocking KV3.4 currents prevented (the neurotoxic β-amyloid peptide1–42) Aβ1−42-induced caspase-3 activation and apoptotic processes ^[48][49].

Moreover, several small peptides are closely associated with the mitochondrial-mediated apoptosis pathway. The hexapeptide FIMGPY (

Table 1

Raja porosa

₅₀ of 4.81 mg/mL. It also could induce apoptosis by upregulating the Bax/Bcl-2 ratio and caspase-3 activation ^[50]. The anticancer peptide AAP-H (

Table 1

Anthopleura anjunae with an amino acid sequence Tyr-Val-Pro-Gly-Pro. It has been shown that AAP-H induces apoptosis by decreasing the mitochondrial membrane potential and increasing Bax/Bcl-2 ratio, cytochrome-C, caspase-3, and caspase-9 ^[51]. An antiproliferative pentapeptide ILYMP (

Table 1

Cyclina sinensis

ILYMP enhances Bax and cleaved caspase-3/9 expression and the suppression of Bcl-2 expression in DU-145 cells ^[52].

Apoptosis is closely related to cell cycle arrest. At present, some small peptides discovered cannot only induce cancer cells apoptosis, but also cause cell cycle arrest and ultimately lead to cell death. The sequences of SCH-P9 and SCH-P10 (

Table 1

Sinonovacula constricta hydrolysates. The researches illustrated that SCH-P9 and SCH-P10 inhibited the growth of DU-145 cells and PC-3 cells by reducing the number of cells in the G0/G1 phase, thus increasing the number in the sub G1 phase and inducing apoptosis ^[53]. SIO (

Table 1

sepia ink. The research found that it significantly inhibited the proliferation of DU-145, PC-3, LNCaP (human prostate cancer cells), A549 and H-1299 cells, in a time and dose-dependent manner by inducing apoptosis and arresting cell at S or G2/M phase ^[54][55]. The anticancer mechanism is similar to another decapeptide SHP, which is accompanied by the activation of cellular tumor antigen p53 and caspase-3, the upregulation of pro-apoptosis regulator Bax, and the downregulation of anti-apoptosis regulator Bcl-2 ^[70]. Psammaplin A (PsA) (

Table 1

Figure 3) is a natural product that has been isolated from sponges and has been suggested to be a promising novel HDAC (histone deacetylase) inhibitor. Some researchers found that PsA exhibited antiproliferative effects on cancer cells by the induction of cell cycle arrest and apoptosis. However, the psammaplin class has the disadvantage of physiologic instability ^[56][57]. Latest research reports that the indole derivatives of Psammaplin are more potent modulators of epigenetic enzymes than the original natural product. Additionally, positional isomers at the bromoindole ring also showed cell cycle block and apoptosis induction ^[57]. NVP-LAQ824 (

Table 1) is a more stable indolic cinnamyl hydroxamate analogue of Psammaplin A, has entered phase I clinical trials in patients with solid tumors or leukemia ^[58]. A toxicity evaluation in rats identified the hematopoietic and lymphatic systems as the primary target organs, with a reversible dose-dependent reduction in RBC (red blood cell) and WBC (white blood cell) counts and lymphoid atrophy ^[58].

2.2. Fungi and Bacteria

Hundreds of secondary metabolites obtained from marine fungal strains revealed potent pharmacological and biological activities ^[71]. Lucentamycins A–D (

Table 1

Figure 3

Nocardiopsis lucentensis

₅₀ values of 0.20 and 11 µM ^[59]. Two highly modified linear tetrapeptides, Padanamides A and B (

Table 1

Table 3

Figure 5

Microsporum

gypseum. Since ring-opening enzymes easily inactivate natural products, many analogues have been synthesized and modified to provide better stability, and 86 analogues have been reported synthesized ^[99]. Recently researchers have shown that Sansalvamide A and Sansalvamide analogues inhibit cell growth and proliferation, and induce cell apoptosis by regulating the expression of HSP90 ^[99][100]. New research has shown that HSP90A strengthens AKT activation through TCLlA-stabilization, promoting multi-aggressive properties in tumor cells ^[104].

Trapoxin (

Table 3

Figure 5

l-Aoe) ^[105][106]. Some finding displayed that the primary target molecule of the agent in vivo is the histone deacetylase itself, and it also induced growth inhibition in several cell lines regardless of their p53 status ^[101][102]. Other cyclic peptides, Microsporins A and B (

Table 3

Figure 5

Microsporum

gypseum

₅₀

_S

₅₀ values of 0.14 and 0.55 µM, respectively ^[103].

3.3. BacteriaBacterial proteins and peptides are a class of promising bioactive compounds and potential anticancer drugs ^[107]. Mixirins are cyclic acyl-peptides derived from the bacterium 

Bacillus

Table 4

Figure 6

₅₀

Table 4

Figure 6

Thermoactinomyces

₅₀

Table 4

Figure 6

Mechercharimyces asporophorigenens

₅₀

Table 3

Figure 6

Salinispora arenicola

₅₀

Figure 6. The structures of marine bioactive cyclic peptides from Bacteria.